AbstractReceptor tyrosine kinases (RTKs), constituting a major family of cell-surface transmembrane receptors, are essential for intracellular tyrosine phosphorylation and signal transduction. RTK signaling is crucial for cellular fate regulation and tissue homeostasis, and its disruption is linked to numerous diseases. Herein, we present a comprehensive review of signaling pathways involving RTKs, with a focus on their signal transduction mechanisms and key components, along with their interactions with major signaling cascades such as G protein-coupled receptors, Wnt, and transforming growth factor β pathways. We also elucidate the multidimensional roles of RTKs in cancer development and progression, highlighting their key effects on cancer stem cell maintenance, tumor microenvironment modulation, and other factors. Furthermore, we systematically summarize the roles of RTKs in noncancerous diseases, including cardiovascular disorders, neurodegenerative diseases, metabolic syndrome, autoimmune conditions, and fibrotic disorders. We then examine current RTK-targeted therapeutics, including small-molecule inhibitors and monoclonal antibodies, for the treatment of various cancers. Finally, novel therapeutic strategies, along with the challenges associated with their development and application, are discussed. In summary, this review will enhance the understanding of the mechanistic aspects of RTK signaling in major disease pathways and provide a detailed overview of recent advancements in targeted therapeutic interventions.IntroductionThe concept of receptor tyrosine kinases (RTKs) emerged during the exploration of growth factor receptor activation and signal transduction mechanisms. In 1980, Stanley Cohen’s work first demonstrated that the EGF receptor intrinsically phosphorylates tyrosine residues in endogenous membrane proteins and exogenous substrates such as histones in A431 carcinoma cells.1 Further research has confirmed the intrinsic tyrosine kinase activity of multiple cell-surface growth factor receptors, including insulin2 and PDGF3 receptors, and established that these receptors form a large RTK family. RTK homologs have been identified across metazoans, with orthologous receptors exhibiting high functional conservation.4,5,6,7 RTKs are typically activated by ligand binding, and they orchestrate cellular fate through tyrosine kinase domain activation and downstream phosphorylation cascades, thereby regulating critical processes, including proliferation, differentiation, survival, migration, cell cycle progression, and metabolism in cells.8 Dysregulated RTK signaling is a well-established pathological feature in numerous human diseases.The mechanistic roles and therapeutic implications of RTKs differ between cancer and noncancerous disorders. In cancer, somatic mutations, gene amplifications, or aberrant activation of RTKs frequently act as primary drivers of oncogenesis and tumor progression.9 Abnormal RTK signaling directly fuels cancer cell proliferation, survival, invasion, and metastasis; it also promotes malignant progression by remodeling the tumor microenvironment (TME), modulating key components, including immune cells, stromal elements, and cytokine networks.10,11 Clinically, RTK-targeted therapies, such as monoclonal antibodies (mAbs) and small-molecule tyrosine kinase inhibitors (TKIs), have revolutionized cancer treatment.12 However, their efficacy is often limited by acquired resistance, tumor heterogeneity, and off-target toxicity, posing significant challenges to treatment durability and patient quality of life.13 In noncancerous conditions, RTK signaling is often a contributor or facilitator of disease progression rather than a primary driver. Nevertheless, emerging evidence highlights the significant involvement of dysregulated RTK pathways in diverse noncancerous conditions, including atherosclerosis,14 Alzheimer’s disease (AD),15 and metabolic syndrome.16 Although RTKs are potential therapeutic targets in the aforementioned contexts, research on their roles as primary therapeutic targets and precise mechanisms of action, as well as viable strategies for their clinical translation, remains in the initial stages.This review provides a systematic overview of RTKs, including their discovery, receptor classification, structural features, critical signaling nodes, and interactions with other pathways. Moreover, the contributions of RTKs to both cancer and noncancerous conditions are delineated, with emphasis on their targetability for disease intervention. Furthermore, we comprehensively demonstrate RTK-targeted therapeutic strategies and evaluate the potential of combinatorial approaches against treatment resistance. By integrating fundamental insights with clinical advances in the field of RTK research, this review establishes a robust foundation for understanding pathogenic mechanisms and developing next-generation targeted therapies.Brief history of RTKSThe foundational exploratory phase of RTK research was from the 1960s to the 1980s. In 1962, Cohen successfully isolated a protein from the submandibular glands of mice and named it epidermal growth factor (EGF) because of its ability to stimulate epidermal cell proliferation.17 In 1976, researchers employed 125I labeling to elucidate, for the first time, the dynamic processes associated with human EGF in fibroblasts, including specific binding, internalization, and degradation, among other critical stages.18 Despite these advancements, the precise molecular mechanisms underlying EGF signal transduction across the cell membrane remained elusive. In 1984, Axel Ullrich and team performed a detailed analysis of the molecular structure of EGF receptor (EGFR) in A431 epidermoid carcinoma cells, which was a major milestone in RTK research.19 The researchers noted that EGFR is a transmembrane protein endowed with tyrosine kinase activity: the extracellular domain of EGFR is responsible for EGF binding and subsequent receptor dimerization, whereas its intracellular kinase domain facilitates growth signal transmission via phosphorylation. The ligand–receptor–kinase cascade model not only established a foundational framework for the functional analysis of EGFR but also emerged as a paradigm for understanding the mechanisms of the entire RTK family.8In the 1980s, research on RTKs and their associated diseases progressed into the mechanistic exploration phase. In 1984, Alan L. Schechter et al. identified that a series of rat neuroglioblastomas harbored the same transforming gene, human EGF receptor 2 (HER2), and proposed its encoded protein as a tumor antigen.20 In 1987, Dennis Slamon and team established a direct correlation of HER2 amplification with the malignant phenotype and poor prognosis in breast cancer.21 Consequently, HER2 was the first RTK gene to be identified as a cancer-driving gene. Moreover, accumulating evidence indicates that dysregulation of RTK function has a role in not only tumorigenesis but also various noncancerous conditions.22,23,24 Through the structural and functional elucidation of other RTK family members, such as AXL,25 vascular endothelial growth factor (VEGF) receptor (VEGFR),26 and TIE2,27 researchers have progressively developed a comprehensive understanding of the role of RTKs in the regulation of both physiological and pathological processes.8Since the late 20th century, the advent of RTK-targeting therapies has marked a significant advancement in medical treatment. In particular, the approval of trastuzumab by the U.S. Food and Drug Administration (FDA) in 1998 was for HER2-positive breast cancer.28 As the first mAb approved for solid tumors, trastuzumab represents a milestone in tailored cancer therapies. Many randomized clinical trials have consistently demonstrated that trastuzumab can significantly improve disease-free survival in women with HER2-positive breast cancer, thereby establishing the value of RTK-targeted therapy.29 Thereafter, substantial progress was achieved in small-molecule TKI development. In 2003, gefitinib received approval for non-small cell lung cancer (NSCLC) treatment, making it the first targeted drug for RTK signaling inhibition via blockade of the tyrosine kinase domain (TKD).30 The introduction of RTK-targeting mAbs and TKIs has considerably broadened the therapeutic options available to patients with cancer.30,31 Efforts to apply this successful therapeutic paradigm have rapidly extended to noncancerous conditions. For instance, pegaptanib, an anti-VEGF RNA aptamer, was approved by the FDA for neovascular age-related macular degeneration (nAMD) treatment in 2004.32 As the first antiangiogenic therapy capable of effectively preserving vision in nAMD patients, pegaptanib not only offered a new treatment paradigm for nAMD but also represented the first validation of an RTK-targeting strategy in a noncancerous context.33 Concurrent efforts to enhance the efficacy and minimize the adverse effects of RTK-targeted therapies have led to the continuous development of a new generation of antibodies and TKIs.34,35,36,37,38Over the past decade, numerous RTK-targeted therapeutics and treatment strategies have been developed, including bispecific antibodies, antibody–drug conjugates (ADCs) and targeted protein degradation (TPD). Concurrent advancements in technologies such as single-cell sequencing, cryoelectron microscopy, and AI-driven structural prediction have significantly enhanced the current comprehension of RTK signaling networks in various diseases and expedited the rational design of targeted therapies. These therapies and their unique advantages are described in later sections of this review. Figure 1 provides a concise overview of discoveries and developments related to RTK signaling.Fig. 1Full size imageMilestones in RTK signaling research and development. Landmark discoveries and therapeutic breakthroughs are chronologically arranged from left to right. The early milestones predominantly feature the EGFR family, reflecting its foundational role in the field. EGF epidermal growth factor, EGFR EGF receptor, HER2 human epidermal growth factor receptor 2, NSCLC non-small cell lung cancer, nAMD neovascular age-related macular degeneration, VEGF vascular endothelial growth factor, T-DM1 ado-trastuzumab emtansine, ADC antibody–drug conjugate, T-DXd trastuzumab deruxtecan. Image created with BioRender (https://biorender.com/)RTK family classificationThe canonical structure of RTKs comprises three main regions: an extracellular region with the ligand-binding site, a single transmembrane helix, and an intracellular domain; the intracellular domain includes a TKD flanked by juxtamembrane regulatory regions and a carboxy (C)-terminal tail. The human genome encodes 58 RTKs, which can be classified into 20 subfamilies based on sequence homology and distinct structural motifs in their extracellular domains, such as immunoglobulin-like domains and fibronectin type III repeats (Fig. 2). Several of the 58 human RTKs form a functionally distinct pseudokinase subfamily.39 Approximately 10% of human protein kinases are predicted to lack phosphotransferase activity due to substitutions of conserved and essential catalytic residues. In particular, five RTKs are definitively classified as pseudokinases: ErbB3/HER3, PTK7/CCK4, EphB6, EphA10, and STYK1.40 ROR1, ROR2, and RYK, which feature substitutions at various essential residues, have also been demonstrated to lack kinase activity and ATP-binding capacity and thus are classified as pseudokinases.41,42,43 Notably, the pseudokinase domain, a degenerate kinase fold lacking catalytic activity, functions as an allosteric regulator and scaffolding protein, which assembles complexes with signaling partners to regulate downstream pathways.44Fig. 2Full size imageStructural classification of RTK family proteins. The human RTK family comprises 20 subfamilies classified by extracellular domain architectures and conserved intracellular TK domains. Structural hallmarks linked to functional specialization are highlighted. To clarify key concepts in RTK biology, the following terms are defined. Juxtamembrane region: A regulatory domain between the transmembrane helix and the kinase domain, often containing autoinhibitory motifs or regulatory phosphorylation sites. Tyrosine kinase domain: The conserved intracellular catalytic core responsible for phosphorylating tyrosine residues on target proteins. Image created with BioRender (https://biorender.com/)Signal transduction in RTK signaling pathwaysLigand binding and dimerizationThe canonical RTK activation paradigm involves ligand–receptor binding, receptor dimerization, trans-autophosphorylation, and subsequent activation of downstream signaling pathways.8 The binding of ligands is the initial event in RTK signaling. These ligands include diverse bioactive molecules, primarily soluble proteins such as hormones, growth factors, and cytokines. Each RTK family has a structurally distinct extracellular ligand-binding domain, ensuring strict ligand selectivity and allowing only specific ligands to interact with the receptor and initiate downstream signaling. This specificity ensures the precision and fidelity of signal transduction, thereby ensuring specific cellular responses to their cognate ligands.45 Although the canonical paradigm of RTK activation involves soluble ligands capable of long-range signaling, several RTK families deviate from this model. These RTK families specialize in direct, contact-dependent communication at the interfaces with the extracellular matrix (ECM) or between cells. For instance, discoidin domain receptors (DDRs) are activated by fibrillar collagen within the ECM, and they exhibit characteristically slow, sustained activation kinetics.46 Moreover, Eph receptors are activated by ephrins anchored to the plasma membrane of adjacent cells. The Eph-ephrin complex orchestrates communication between similar or different types of cells through unique bidirectional (i.e., forward–reverse) signaling.47,48 Table 1 comprehensively summarizes RTK families and their cognate ligands.Table 1 RTK subfamily members and corresponding ligandsFull size tableReceptor dimerization has conventionally been considered to be initiated by ligand binding, a process crucial for downstream signaling pathway activation.9 However, certain RTKs can form dimers or oligomers independent of their ligands’ presence. For instance, insulin receptor (InsR) and insulin-like growth factor (IGF) 1 receptor (IGF1R) are present as disulfide-linked dimers on the cell surface. After ligand binding, these preformed dimers undergo conformational changes, leading to intracellular TKD activation and downstream signaling pathway initiation.49 Notably, other RTK subfamilies, such as Eph receptors50 and TIE2,27 can form preassembled oligomeric clusters at the plasma membrane. These preexisting dimers or oligomers can exist in either inactive or active conformational states that are in a dynamic equilibrium. Ligand binding primarily activates the inactive state and stabilizes the active conformation.51,52 These findings indicate that RTK dimerization or oligomerization is not universally dependent on ligand binding. Nevertheless, ligand interactions remain crucial for the activation of most RTKs under physiological conditions.8 In summary, ligand binding elicits the key activating signal, inducing or stabilizing receptor dimerization–oligomerization—the prerequisite for intracellular TKD trans-autophosphorylation and ultimate activation.TKD activationTKD functions as the catalytic core of RTKs. This enzymatic center drives signaling by catalyzing ATP-dependent trans-autophosphorylation and subsequent phosphorylation of cytoplasmic substrate proteins.8 Structurally, the canonical TKD is a bilobed fold comprising an N-terminal lobe (N-lobe) and a C-terminal lobe (C-lobe).53 The activation loop (A-loop), a critical regulatory element, is anchored within the C-lobe and controls access to the catalytic center. Although the activation mechanisms vary among different RTKs, the crystal structures of their TKDs in their active states are highly conserved.54,55,56,57,58 In this conformation, key regulatory elements such as the A-loop and αC-helix adopt a specific, conserved arrangement, which is essential for efficient catalytic phosphotransfer.59Although the active conformations of RTKs are highly conserved, their inactive-state TKDs exhibit remarkable structural diversity, reflecting the unique regulatory mechanisms inherent to each RTK family member. Before activation, each TKD remains in a state of cis-autoinhibition through distinct intramolecular interactions determined by its own structure and adjacent regulatory elements. Despite the diversity in their autoinhibitory mechanisms, all RTKs are governed by a common principle: blocking the access of ATP and substrates to their catalytic core through direct physical blockade of the active site or indirect allosteric suppression of its activity. One of the canonical autoinhibition mechanisms is mediated by the A-loop within TKD, as observed in receptors such as fibroblast growth factor receptor (FGFR), InsR, and IGF-1R.53,59,60,61 In these receptors, an unphosphorylated A-loop directly inhibits the catalytic function of TKD through intramolecular interactions. In addition to the A-loop within TKD, intracellular regulatory segments flanking TKD, including the juxtamembrane sequence and C-terminal tail, contribute to preactivation autoinhibition in specific RTK subfamilies. The most well-characterized form of this process is juxtamembrane autoinhibition, observed in receptors including muscle-specific kinase (MuSK), KIT, Eph, PDGFRα, and Flt3.62,63,64,65,66 In these receptors, the juxtamembrane region engages in extensive interactions with TKD elements, constraining the kinase in an inactive state. Another form of cis-autoinhibition mediated by elements outside the core TKD is C-tail-mediated autoinhibition, which has been reported in RON, PDGFRβ, and TIE receptors.67,68,69,70 The C-terminal tail of these receptors makes contact with their TKD’s active site, thereby physically blocking substrate access. Following activation, the phosphorylated C-terminal tail primarily serves as a multifunctional docking platform for downstream signaling proteins. Ligand binding induces receptor dimerization, and the resulting conformational change relieves the aforementioned autoinhibition, thereby enabling complete receptor activation through trans-autophosphorylation. The EGFR family constitutes an exception in its activation mechanism: it forms an asymmetric dimer in which the “activator” kinase allosterically activates the “receiver” kinase without requiring A-loop phosphorylation.71In certain instances, RTKs can be activated in a ligand-independent manner.9 A predominant mechanism underlying this activation is driven by overexpression. For instance, HER2 overexpression enables spontaneous dimerization, which leads to receptor autophosphorylation and sustained downstream signaling activation independent of ligand engagement.72 This phenomenon has been extensively documented, particularly among the members of the RTK subfamilies EGFR and MET.73,74,75 Given the widespread amplification of RTKs in various cancers, this mechanism is particularly prevalent in several cancers. It plays a critical role in the activation of multiple oncogenic signaling pathways responsible for essential biological processes, such as cell proliferation promotion, apoptosis inhibition, cell migration enhancement, and angiogenesis.9 Genetic rearrangements or mutations in specific RTKs can confer structural alterations driving ligand-independent dimerization and activation. These structural aberrations typically induce constitutive receptor activation through distinct mechanisms. For instance, RET rearrangements generate fusion proteins (e.g., KIF5B-RET and CCDC6-RET) that introduce coiled-coil domains within their extracellular regions, enabling homodimerization and ligand-independent activation of the RET kinase domain.76 Alternatively, oncogenic RON splice variants with truncated extracellular domains adopt conformational states that permit spontaneous tyrosine kinase activation.77 Beyond extracellular modifications, mutations in the kinase domain A-loop or deletions in the juxtamembrane region can destabilize autoinhibitory conformations. The FGFR1 D647N mutation, located within the A-loop, induces ligand-independent receptor phosphorylation and downstream signaling, considerably enhancing cancer cell invasiveness and proangiogenic capacity.78 Similarly, EGFR insertion mutations (e.g., N771_P772insN and D770_N771insG) activate the kinase via a dimer interface-dependent mechanism by disrupting critical autoinhibitory interactions governing αC-helix movement.79Downstream RTK signaling pathways and their biofunctionsAfter autophosphorylation, RTKs recruit and activate various downstream signaling proteins. Of them, many contain Src homology 2 (SH2) or phosphotyrosine-binding (PTB) domains, which specifically recognize and bind to phosphorylated tyrosine residues on the receptors.80,81,82 These signaling proteins may directly engage phosphotyrosines, or they may become indirectly recruited through docking proteins that are physically associated with RTKs. Critical docking proteins in RTK signaling cascades function as molecular hubs to amplify and diversify signaling outputs, with notable examples including insulin receptor substrate 1 (IRS1),83 fibroblast growth factor receptor substrate 2 (FRS2),80 growth factor receptor-bound protein 2 (GRB2),84 GRB2-associated binder (GAB),85 and SHC.86 Accumulating evidence reveals that RTK signaling networks exhibit far greater complexity than previously recognized.8 The interplay of effector molecules across various signaling pathways forms an intricate regulatory network, enabling cells to respond with precision to external stimuli and execute adaptive responses.To provide a basic framework for understanding RTK signaling and the biological functions of these downstream pathways, a brief overview of the five major RTK downstream signaling pathways is presented in subsequent sections. The pathways include mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT), phospholipase C (PLC) γ, Janus kinase (JAK)–signal transducer and activator of transcription (STAT), and nuclear factor kappa B (NF-κB; Fig. 3). Notably, these pathways do not function as discrete linear signaling cascades. Multidimensional crosstalk between downstream effectors and functional modules of RTKs orchestrates a sophisticated, highly integrated, dynamic regulatory network.Fig. 3Full size imageRTK downstream pathways and main biofunctions. JAK Janus kinase, STAT signal transducer and activator of transcription, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol 3-kinase, NF-κB nuclear factor kappa B, PLC phospholipase C. Image created with BioRender (https://biorender.com/)MAPK pathwayThe MAPK pathway is a critical component of RTK signaling. The GRB2-SOS complex is a central hub linking many RTKs to the RAS-RAF-MEK-ERK phosphorylation cascade.87 Some RTKs, such as EGFR, have a phosphotyrosine motif that directly binds to the SH2 domain of GRB2.88 In contrast, many other RTKs, such as InsR and FGFR, recruit GRB2-SOS indirectly by first phosphorylating docking proteins such as IRS family proteins or FRS2, which then provide GRB2-binding sites.89,90 After phosphorylation, ERK translocates into the nucleus, activates transcription factors (e.g., c-Fos and c-Jun), promotes the expression of cell cycle proteins such as cyclin D1, and drives the transition of cells from G1 to S phase, thereby accelerating proliferation.91 RTKs regulate numerous key physiological processes, including proliferation, differentiation, development, inflammation, apoptosis, and stress response, through the MAPK pathway.PI3K-AKT pathwayThe PI3K-AKT pathway is a central effector mechanism downstream of RTK activation. RTK autophosphorylation leads to the recruitment of PI3K, which catalyzes PIP3 synthesis to activate AKT. AKT further regulates downstream molecules, such as mTOR and glycogen synthase kinase (GSK) 3β, to mediate various biological processes, such as cell proliferation, survival, metabolism, migration, and apoptosis inhibition.92 Aberrant activation of the PI3K-AKT pathway is often associated with various cancers, and its overactivation is strongly linked to tumor cell growth and treatment resistance.93 Most RTKs promote proliferation and survival by activating survival MAPK and PI3K-AKT pathways. Diverging from the canonical paradigm, ligand-bound EphA2 suppresses both the PI3K-AKT and MAPK pathways in diverse cellular contexts and attenuates platelet-derived growth factor (PDGF)-, EGF-, and VEGF-induced activation of these two pathways.94,95,96,97PLCγ pathwayThe PLCγ pathway is a crucial RTK signaling pathway. PLCγ binds to RTKs through the SH2 domain, and then PLCγ hydrolyzes PIP2 to generate IP3 and DAG. IP3 triggers Ca2+ release, and DAG activates protein kinase C (PKC), regulating cell proliferation, survival, angiogenesis, and autophagy.98,99 PLCγ plays a crucial role in endothelial, immune, neuronal, and cancer cells, and abnormalities in its function are often associated with various diseases.99,100,101JAK-STAT pathwayThe JAK-STAT pathway is another key cellular signal transduction pathway involved in the regulation of various biological processes, including immune response, proliferation, differentiation, survival, and stress response. After cytokine stimulation, JAKs can promote STAT phosphorylation; then, STATs enter the nucleus to regulate target gene transcription.102 Activation of some RTKs, including EGFR, MET, FGFR, IGF receptor (IGFR), and PDGFR, can directly phosphorylate STAT tyrosine in a JAK-independent manner, considerably enhancing the transcriptional activity of STATs.103,104,105NF-κB pathwayProteins from the transcription factor family NF-κB play key roles in crucial biological processes such as immunity, inflammatory response, and tumorigenesis.106 RTKs can modulate NF-κB signal transduction through various mechanisms. In particular, they can either enhance or attenuate NF-κB signaling depending on the context. During tumorigenesis, RTKs typically facilitate tumor progression by activating NF-κB. For instance, in EGFR-mutant lung cancer, aberrant EGFR signaling strongly activates NF-κB, which is crucial for tumor cell survival and promotes resistance to targeted therapies.106 In hepatocellular carcinoma (HCC), the MET receptor enhances cancer initiation and metastasis by upregulating TAK1 and activating the NF-κB pathway.107 Furthermore, NF-κB is a downstream effector molecule within the PI3K-AKT-mTOR pathway.108,109,110 AKT activation is pivotal in mediating various tumorigenic functions associated with NF-κB. For instance, mTOR modulates NF-κB activity in PTEN-deficient prostate cancer cells by interacting with IKK and subsequently stimulating IKK activity. The mTOR-associated protein Raptor is essential for AKT-mediated induction of NF-κB activity.111 In summary, the PI3K-AKT pathway has a significant role in RTK-mediated regulation of NF-κB. During inflammation, RTKs, such as MET, RON, and TAM (TYRO3, AXL, and MERTK) family members, inhibit NF-κB, attenuating immune and inflammatory responses.11,112,113 Genes encoding proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, are canonical targets of NF-κB.106 In mouse macrophages, MET family receptors (MET and RON) activate the transcription of the orphan nuclear receptor small heterodimer partner, blocking the entry of p65 into the nucleus and diminishing lipopolysaccharide-induced inflammatory responses.114Determinants of signaling pathway specificityGiven the extensive and highly interconnected signaling network downstream of RTKs, a classical question regarding RTK signaling specificity arises: If most RTKs converge into a common set of core pathways, such as the MAPK and PI3K-AKT pathways, how can the activation of distinct RTKs within the same cellular context elicit considerably different biological responses? Conversely, how can the activation of a given RTK provoke divergent outcomes across different cell types? This section, therefore, delineates the current understanding of the mechanisms enabling activated RTKs to achieve signaling specificity through selective engagement of downstream pathways and thereby elicit precise biological responses. Herein, we provide an overview of the overarching principles and frameworks that ensure this specificity rather than delving into exhaustive molecular mechanistic details.Differential downstream recruitmentA primary mechanism ensuring specificity in RTK signaling is the differential recruitment of downstream effector proteins.115,116 Typical RTKs possess 5–12 intracellular autophosphorylation sites that are specific docking points for effector proteins harboring SH2 or PTB domains. A wide spectrum of RTKs recruits adaptors such as Gab1, whereas other adaptors demonstrate high specificity for distinct receptor subfamilies. For instance, IRS family proteins specifically mediate downstream signaling for insulin and IGF-1 receptors,117,118 whereas FRS2 family proteins specifically transduce signals for FGFR and nerve growth factor receptor (NGFR).119,120 Currently, the specificity of interactions between RTKs and their downstream proteins is believed to mainly be determined by the primary sequence surrounding the phosphorylated tyrosine residues of RTKs.121Signal duration and amplitudeDownstream signaling intensity and duration are also key determinants of the specific biological effects of RTK signaling. A classic example is the differential dynamics of MAPK signaling mediated by RTKs in PC12 cells, which directly determine cell fate. Receptors such as EGFR and InsR trigger transient MAPK activation, leading to cell proliferation, whereas receptors such as NGFR and FGFR induce sustained MAPK activation, promoting neuronal differentiation.122 This difference is primarily achieved through the RTK-mediated differential activation of positive and negative regulatory factors, such as PKC, within the MAPK network.123 These dynamic regulatory mechanisms allow RTKs to mediate distinct biological outcomes through shared hub molecules.91 The dynamic balance of positive and negative feedback loops is crucial for the precise regulation of RTK signaling.124 The positive feedback mechanisms amplify signal cascades, enhancing cellular responsiveness to RTK signaling.124 In contrast, negative feedback mechanisms contribute to the robustness of RTK signaling, preventing excessive signal activation.8 Ubiquitin-mediated degradation is a key mechanism of such negative feedback-based regulation. After endocytosis, ubiquitinated receptors are typically directed to the lysosome for degradation, thereby attenuating the signals.12 Disruption of this mechanism can lead to persistent RTK activation.125 For instance, the E3 ubiquitin ligase CBL, a key ubiquitination regulator of RTKs, recognizes phosphorylated tyrosine residues and mediates their ubiquitination, which promotes RTK degradation. However, oncogenic variants of TPR-MET disrupt c-CBL-mediated ubiquitination via phenylalanine substitution at the juxtamembrane tyrosine; this blocks degradation and drives constitutive transforming activity in fibroblasts and epithelial cells.126Spatial regulationIn recent years, the role of spatial regulation in RTK signaling has gained considerable attention. Lipid rafts, which are microdomains enriched with cholesterol and sphingolipids, act as key assembly centers for signal transduction complexes,127 and they influence RTK localization and activity.128,129 For instance, in HCC, CD317 plays a crucial role in modulating EGFR release from lipid rafts; this promotes EGFR activation and downstream signaling pathway initiation, facilitating cell cycle progression and enhancing tumorigenic potential in an EGFR-dependent manner.130 In addition, lipid rafts may be involved in resistance to RTK-targeting small-molecule inhibitors due to abnormal cholesterol synthesis in cancer cells.131RTK activation and signaling have been traditionally posited to predominantly occur at the cell membrane. However, emerging evidence indicates that RTKs also perform unique, nonredundant functions within the perinuclear endosome and nucleus.132,133,134,135 Hepatocyte growth factor (HGF)-dependent movement of STAT3 into the nucleus requires transportation of c-MET to the perinuclear compartment rather than initiation through phosphorylation at the plasma membrane and diffusion from activated c-MET.133 Clathrin-mediated endocytosis is essential for EGFR-activated AKT and MAPK pathways, suggesting that these events occur predominantly within endosomes.136 These findings underscore the need for a comprehensive understanding of the distinct roles of RTKs across various subcellular compartments.Cellular contextNotably, the biological effects of an RTK can vary considerably across different cell types and even within different differentiation stages of cells from the same lineage.137,138 This heterogeneity is mainly determined by the number, structural characteristics, and binding kinetics of the receptor–ligand pairs involved in signal transduction.139 Nevertheless, the final output of the response strongly depends on the inherent state of the cell, namely, the cellular context, which encompasses all effector proteins, transcription factor networks, epigenetic background, and metabolic state of the cell. Therefore, one RTK signal input may be decoded as diverse instructions by the internal environments of different cells, triggering substantially distinct programs such as proliferation, differentiation, survival, or migration.In summary, RTK signaling specificity is not determined by a single factor but arises from a multilayered regulatory system. However, because this system is highly complex, fully predicting the dynamic behavior of RTK downstream networks and their eventual biological effects through quantitative modeling remains a major challenge.8,140,141,142 In recent years, the rapid development of artificial intelligence (AI) has offered transformative opportunities to simulate RTK signaling networks through the integration of various quantitative omics and computational modeling approaches, particularly with AI virtual cell-enabled visualization.143,144,145 The ability of AI to process large volumes of multimodal data may afford a deeper understanding of RTK signaling pathways in human diseases. Consequently, AI integration can drive the development of precision therapies, facilitate the prediction and management of resistance mechanisms, and enable the design of personalized treatment plans for each patient.146,147Crosstalk of RTK and other signaling pathwaysRTK and other signaling pathways demonstrate extensive interactions, which significantly influence cell fate, including proliferation, differentiation, and survival. These interactions are also intricately linked to the onset and progression of various diseases. Here, we focus on prototypical crosstalk patterns with well-defined mechanisms and pathological relevance. In particular, the interactions of RTKs with the G protein-coupled receptor (GPCR), Wnt, and transforming growth factor β (TGF-β) pathways are summarized.GPCR pathwayGPCRs, constituting one of the largest families of membrane proteins, can mediate various extracellular stimuli, including ions, neurotransmitters, hormones, lipids, peptides, and light.148 Consequently, GPCRs are integral to numerous pathophysiological conditions.149,150 As illustrated in Fig. 4, the interplay between GPCRs and RTKs is bidirectional and intricate. GPCRs act as upstream regulators that transactivate RTKs through multiple mechanisms. In particular, GPCR-activated metalloproteinases induce the shedding of the extracellular domain of membrane-bound ligands, such as EGF,151,152,153,154,155 leading to ligand-dependent transactivation. Moreover, ligand-independent transactivation involves GPCR activation, which stimulates cytoplasmic non-RTKs, including c-Src and PYK2, which then facilitate the tyrosine phosphorylation of RTKs, such as EGFR156,157 and PDGFR.158 Furthermore, the increased production of reactive oxygen species (ROS) induced by GPCR activation can also facilitate the activation of various RTKs; however, this effect exhibits lower selectivity.159,160,161 GPCR signaling components can also act as transmitters for RTK signaling, adding another layer of complexity to GPCR–RTK crosstalk.162 For instance, IGF1R drives the activation of downstream signaling pathways by directly activating Gi proteins and inducing the release of the Giβγ subunit, eventually triggering the MAPK pathway and mitotic signaling.163,164 Accumulating evidence also indicates that selected RTKs, including EGFR,165 PDGF receptor (PDGFR) β,166,167 IGF1R,168 and TRKA,166 can engage GRKs and β-arrestin-associated mechanisms to mediate signaling.Fig. 4Full size imageCrosstalk between RTKs and GPCRs. Mechanistic interactions between RTKs and GPCRs mainly encompass a GPCR-mediated RTK transactivation, b RTK-GPCR heterocomplex formation, and c G protein-dependent downstream signaling. Image created with BioRender (https://biorender.com/)Notably, the intricate bidirectional crosstalk between RTKs and GPCRs increases their functional complexity, but it also provides new avenues for targeted therapies.169 For instance, TRKB–GPCR crosstalk is critical in the regulation of neuronal function in neurodegenerative disorders.170 Antonijevic et al. recently proposed that developing small molecules that can cross the blood–brain barrier (BBB) and modulate the GPCR-mediated brain-derived neurotrophic factor (BDNF)/TRKB pathway may be a novel strategy for treating these complex conditions.15Wnt pathwayThe Wnt pathway regulates various essential biological processes, including cell proliferation, differentiation, migration, and embryonic development.171 The Wnt pathway model of signal transduction via the coreceptors FZD and LRP5/6 has been widely elucidated. The classical Wnt pathway enhances β-catenin stability, which typically requires coreceptor participation.172 RTKs and the Wnt pathway engage in crosstalk critical for epithelial repair, growth, and development, as well as oncogenesis.173,174 AKT, a well-established effector molecule within the RTK signaling pathway, is a GSK3β inhibitor.175 RTK activation leads to β-catenin stabilization via the PI3K-AKT-GSK3β cascade, enhancing canonical Wnt signal transduction.174,176 Furthermore, certain RTKs, such as ROR2, PTK7, RYK, and MuSK, are coreceptors or alternative receptors for Wnt ligands.177,178 For instance, the extracellular domain of ROR2 interacts with Wnt5a, facilitating cell migration in a filamin A-dependent manner.179,180 Moreover, the Wnt-RYK signaling axis is implicated in regulating a wide variety of developmental processes, including axon guidance and craniofacial and musculoskeletal structure morphogenesis.177 The identification of RTKs as additional receptors for Wnt ligands has provided novel insights into Wnt signal transduction in the contexts of both developmental biology and diseases.177TGF-β pathwayThe TGF-β pathway exerts its functions through receptor-mediated activation of SMAD proteins, demonstrating a context-dependent duality in cancer. It not only suppresses tumorigenesis in normal cells but also promotes invasion and metastasis in advanced stages of cancer.181,182 The functional outcome of this pathway is mainly shaped by its intricate crosstalk with RTK signaling, and this crosstalk occurs at multiple levels. TGF-β can transcriptionally upregulate RTK ligands such as EGF and PDGF, establishing an autocrine feed-forward loop that sustains mitogenic signaling.183 Furthermore, TGF-β can directly activate canonical RTK effector pathways, including the MAPK and PI3K-AKT pathways, through non-SMAD mechanisms.184 Reciprocally, RTK-activated kinases such as ERK and AKT can phosphorylate SMAD proteins in their linker regions, thereby positively or negatively regulating SMAD transcriptional activity and nuclear localization.185,186,187 Notably, certain oncogenic RTK mutations can drive the upregulation of TGF-β expression, fostering resistance to targeted RTK inhibitors via bypass mechanisms.188,189 A main biological output of this crosstalk is the synergistic induction of epithelial–mesenchymal transition (EMT), which is crucial in cancer progression and fibrosis.190,191 A recent study exemplified the complexity and therapeutic relevance of this interaction by demonstrating that TGF-β promotes TRKB degradation in hepatic stellate cells (HSCs) via the E3 ubiquitin ligase Nedd4-2. Notably, TRKB overexpression inhibits the activation of the TGF-β-SMAD pathway and alleviates hepatic fibrosis, highlighting its therapeutic potential for targeted interventions.24 Therefore, future studies focused on systematically dissecting the interactions between RTKs and TGF-β across diverse disease models in the cellular context are warranted. Their results may aid in elucidating universal principles and context-specific patterns of RTK-TGF-β interactions, thereby enabling the development of broadly applicable RTK-based therapeutic strategies.RTK signaling in diseasesAs pivotal regulators of organismal development and tissue homeostasis, RTKs demonstrate pathophysiological significance across various organ systems, including cardiovascular, respiratory, neurological, digestive, endocrine, and urinary systems. Extensive research has revealed the pivotal role of RTK dysregulation in tumorigenesis, with functional abnormalities often arising from mechanisms such as gene mutations, autocrine or paracrine stimulation, and receptor overexpression. These factors collectively create a favorable environment for cancer progression. Tomuleasa et al. extensively reviewed the molecular alterations of individual RTKs in cancer; however, a detailed discussion of these aspects is beyond the scope of the current review. Abnormal activation of RTKs has also been implicated in the onset and progression of various noncancerous conditions. In recent years, molecular targeted therapies directed at RTKs have demonstrated clinical potential in treating several noncancerous conditions; however, a systematic elaboration of their therapeutic landscape is currently lacking. The subsequent sections focus on the key pathological processes underlying cancer development and progression in which RTKs play a central role, providing a comprehensive perspective on their function as integrative hubs (Fig. 5). We also elaborate in detail on the pivotal roles of RTKs in noncancerous conditions, focusing on major conditions where targeted RTK therapies have demonstrated efficacy or potential for further exploration (Fig. 6).Fig. 5Full size imageRTK signaling in cancer pathogenesis. RTK signaling pathway hyperactivation promotes oncogenesis via modulation of stemness maintenance, EMT epithelial–mesenchymal transition, TME remodeling, angiogenesis, metabolic reprogramming, and therapeutic resistance. α-SMA α-smooth muscle actin, MMPs matrix metalloproteinases, TIMPs tissue inhibitors of metalloproteinases, MDSC myeloid-derived suppressor cell, BCRP breast cancer resistance protein, TCA tricarboxylic acid, CRCC chemotherapy-resistant cancer cell. Image created with BioRender (https://biorender.com/)Fig. 6Full size imageRTK signaling in noncancerous diseases. RTK signaling contributes to the regulation of noncancerous diseases affecting multiple organ systems, including the digestive, endocrine, musculoskeletal, nervous, respiratory, cardiovascular, and urinary systems, along with other physiological systems. Image created with BioRender (https://biorender.com/)RTKs in cancer and tumorigenesisCancer stem cellsCancer stem cells (CSCs) exhibit traits analogous to those of normal stem cells, such as self-renewal and sustained proliferative capacity.192 CSCs also act as pivotal drivers of tumor relapse and metastasis by switching between quiescent and proliferative states, evading immune surveillance, and resisting conventional therapies.193 RTKs, which are crucial signaling regulators of stem cell self-renewal, are believed to play a central role in governing the properties of CSCs through their aberrant activation. By driving EMT, RTKs enhance cancer cell heterogeneity and adaptability, allowing non-CSCs to attain stem-like traits. Simultaneously, RTKs effectively promote CSC self-renewal and stemness maintenance.194 For instance, in glioblastoma (GBM), EGF induces TAZ expression in stem-like cells via the EGFR-ERK/STAT3 pathway, endowing them with ectopic, mitogen-independent growth and self-renewal capabilities. This process promotes tumor invasion, radiation resistance, and tumorigenicity. The EGFR inhibitor osimertinib blocks the EGFR-TAZ axis, effectively suppressing the growth of these stem-like cells in vivo.195 Tumor biomechanical abnormalities are key physical attributes of malignancies.196 Recent studies have indicated that DDR1 sustains stem cell phenotypes by promoting ECM organization and remodeling, thereby facilitating immune evasion.197,198 Targeting RTK-mediated biomechanical microenvironments in CSCs may thus be a novel therapeutic strategy to overcome resistance in clinical cancer treatment.EMTEMT is considerably implicated in cancer progression because it facilitates the conversion of cancer cells from an epithelial phenotype to a mesenchymal phenotype, thereby augmenting the migratory, invasive, and metastatic potential of tumors. This transition is frequently accompanied by resistance to chemotherapeutic agents.199,200 Recent evidence indicates that after activation by growth factors, including EGF, FGF, IGF, PDGF, and GAS6, several RTKs183,201,202 promote EMT and the associated drug-resistant phenotypes through downstream signaling cascades. As outlined in the “Crosstalk of RTK and other signaling pathways” section, although TGF-β and the aforementioned growth factors signal through distinct receptors, the functional consequences of TGF-β signaling are strongly modulated by its intricate crosstalk with RTK pathways, which results in synergistic regulation of EMT. Moreover, RTK signaling sustains the plastic state of cancer cells during this process, conferring a hybrid phenotype with both epithelial and mesenchymal traits and increasing adaptive capacity.203,204 This plasticity is a major contributor to tumor heterogeneity and treatment resistance. Therapeutic targeting of RTKs can reverse EMT and resensitize cancer cells to various small-molecule inhibitors and chemotherapeutic drugs.204 For instance, in NSCLC, AXL activation induces EMT through activation of the AKT, MAPK, and NF-κB pathways, thereby mediating resistance to EGFR-targeting drugs.205 Inhibiting AXL can reverse this resistance, restoring cellular sensitivity. In summary, EMT synergistically drives tumor invasion, metastasis, and therapeutic resistance. As a key regulatory component of EMT, RTKs represent critical targets for reversing malignant phenotypes and overcoming drug resistance.AngiogenesisHypoxia within the TME upregulates the expression of several hypoxia-inducible transcription factors (HIFs), which subsequently drive the transcription of downstream proangiogenic factors, including VEGF, PDGF, and FGF2.206,207 These secreted factors activate RTKs in tumor endothelial cells and pericytes and synergize with other pivotal proangiogenic pathways, such as the Notch and Wnt pathways, promoting proliferation, migration, and tumor neovascularization. This angiogenic process provides essential nutrients to support tumor growth and facilitates the intravasation of malignant cells into the circulation.208 However, the vasculature generated through RTK-driven angiogenesis is frequently structurally and functionally aberrant and characterized by compromised perfusion and intensified localized hypoxia.208,209 This hypoxic state, in turn, amplifies RTK signaling further, eventually establishing a self-sustaining vicious cycle. Moreover, RTK signaling pathways (such as the VEGFR pathway) can inhibit endothelial cell adhesion molecules by suppressing key transcription factors such as NF-κB. This endothelial dysfunction leads to impairment in the ability of T cells to extravasate and enter the TME.210 Preclinical studies have confirmed that antiangiogenic therapy, alone or in combination with immunotherapy, enhances antitumor immunity by promoting T-cell infiltration.211TMEThe TME encompasses the surrounding milieu of tumor cells, comprising nearby blood vessels, immune cells, fibroblasts, myeloid-derived inflammatory cells, diverse signaling molecules, and the ECM.212 The crosstalk between cancer cells and their TME is mediated by multiple signaling pathways, including the RTK, TGF-β, and cGAS-STING pathways. RTK signaling orchestrates macrophage polarization toward the M2 phenotype and induces functional exhaustion in T cells and natural killer (NK) cells, thereby promoting immunosuppressive and protumor outcomes. Furthermore, RTK signaling modulates the activities of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells, which collectively facilitate tumor immune escape.213 Cao et al. discovered that doramitinib, a multitarget RTK inhibitor, can activate the SNAI1/2-IFN-γ axis within cancer cells. This transformation converts immune-desert tumors into immune-inflamed ones, attracting T cells into the TME and rendering previously resistant cold tumors sensitive to CTLA-4 inhibitors.214 This finding demonstrates that RTK inhibitors can alleviate immune suppression by reshaping the TME, thereby facilitating subsequent immunotherapy. Cancer-associated fibroblasts (CAFs) represent crucial stromal components within the TME. DDR1 and DDR2 activation in CAFs modulates ECM production and remodeling,215 thereby promoting tumor rigidity and altering anticancer immunity. Simultaneously, CAFs, along with other stromal cells, secrete various RTK ligands that persistently activate RTK receptors on tumor cells and neighboring cells.216 This sustained signaling promotes the establishment of new vascular networks, further reinforcing tumor growth and metastatic dissemination in cancer.Metabolic reprogrammingCancer cells autonomously reprogram their metabolic pathways to fulfill increased demands for bioenergy and biosynthesis and mitigate oxidative stress, a process critical for cancer cell proliferation and survival.217 Through aberrant RTK activation, tumors alter metabolic circuits to directly support cancer cell growth and survival adaptations. These metabolic alterations further disrupt immune responses, promoting immune evasion and metastatic progression.218 Notably, RTK activation can modulate specific metabolic pathways, and the resulting metabolic reprogramming may establish unique therapeutic vulnerabilities, which can be harnessed for targeted intervention. For instance, transcription factor–mediated differential expression of metabolic genes can induce RTK-associated metabolic heterogeneity.219 FGFR-activated tumors exhibit a high dependence on glycolysis for lactate synthesis, with oncogenic signaling primarily centered on MYC. EGFR-activated tumors depend on the serine pathway, preferentially engaging ATF4 to reprogram metabolic networks. These insights offer novel directions for developing precision anticancer strategies and hold significant translational value for guiding patient stratification based on metabolic inhibitors.Chemotherapy resistanceChemotherapy is one of the primary treatment modalities for cancer; however, patients frequently develop resistance to chemotherapeutic agents, severely limiting their therapeutic efficacy and often leading to treatment failure and disease recurrence.220 Aberrant RTK signaling contributes to chemotherapy resistance in malignant tumors. RTK signaling induces cancer cell dormancy, inhibits apoptosis, enhances DNA repair capacity, upregulates drug efflux pump activity, promotes EMT, and facilitates the survival and proliferation of chemotherapy-resistant CSCs, eventually promoting tumor resistance.221 Furthermore, RTKs indirectly contribute to chemoresistance by altering tumor vascular endothelial cell function, exacerbating intratumoral hypoxia, and remodeling the TME.222 For instance, chemotherapeutic agents such as etoposide (VP16) and cisplatin markedly upregulate AXL expression in acute myeloid leukemia models, suggesting that AXL induction may represent an adaptive response to chemotherapeutic stress.223 Clinical evidence further suggests that AXL inhibitors can resensitize tumors to chemotherapy.224 Moreover, AXL inhibitors combined with chemotherapy can significantly suppress tumor proliferation, reduce disease burden, and prevent treatment resistance development.225 Therefore, combining RTK inhibitors with chemotherapy may be a promising therapeutic strategy to overcome clinical chemotherapy resistance.RTKs in vascular diseasesAtherosclerosisAtherosclerotic cardiovascular disease remains a leading cause of death and disability worldwide. In this condition, the formation and progression of core pathological plaques are mainly driven by the combined effects of long-term dyslipidemia and chronic inflammation.226 Current clinical strategies for cardiovascular risk reduction are primarily centered on dyslipidemia management, with statins being the cornerstone first-line therapeutic agents. Research on RTK-targeting therapeutic strategies for atherosclerosis treatment remains mainly preclinical, based on in vitro and in vivo models. Nevertheless, accumulating evidence underscores the critical role of RTKs across nearly all stages of atherosclerosis progression, from the initial stage of endothelial dysfunction to the advanced stage of plaque formation. Notably, targeted inhibition of some RTKs has demonstrated potential in attenuating disease progression or promoting plaque regression in atherosclerosis.The early manifestations of atherosclerosis mainly include endothelial dysfunction, cholesterol lipoprotein deposition, and increased inflammatory response of the vascular wall.227 Altered cholesterol metabolism and chronic inflammatory responses are considered key drivers during the pathological progression of atherosclerosis. Although these processes are significantly correlated during atherosclerosis progression, their causal relationship remains unclear. Nevertheless, evidence suggests that RTKs are involved in these processes. EGFR, for instance, plays crucial proatherosclerotic roles by regulating intracellular cholesterol homeostasis and inflammatory responses. EGFR activation in macrophages promotes oxidized low-density lipoprotein (ox-LDL) uptake and foam cell formation via ERK signaling.14 In contrast, in CD4+ T cells, EGFR signaling drives their activation and proinflammatory factor secretion.228 Notably, the EGFR inhibitor erlotinib significantly reduced the size of atherosclerotic plaques formed at the aortic sinus in an Ldlr-knockout female mouse model on a high-fat diet, without significant adverse effects.229 Because patients are more likely to present at the stable plaque stage than at the early lesion stage, the ability of EGFR inhibitors to reduce already formed plaques highlights their clinical value as therapeutic agents for atherosclerosis treatment. EphA2 expression is upregulated in endothelial cells and vascular smooth muscle cells in human and mouse models of atherosclerosis, promoting inflammatory responses and monocyte adhesion.230,231 Nevertheless, in mice fed a high-fat diet, administration of the EphA2-specific inhibitor ALW-II-41-27 was observed to improve hepatic cholesterol transport and inflammatory profiles, significantly reducing atherosclerotic plaque formation and enhancing plaque stability.232Distinct RTKs exert divergent effects on atherosclerosis. For instance, the FGF21-FGFR1 axis promotes adiponectin secretion from adipose tissue and inhibits NF-κB to reduce vascular inflammation, providing anti-atherosclerotic effects.233 ROR2 promotes disease progression by downregulating ABCA1 expression and facilitating NF-κB nuclear translocation, leading to lipid accumulation and inflammation.234 Thus, ROR2 inhibition may represent a potential therapeutic approach for treating or alleviating atherosclerosis. TIE family proteins primarily regulate inflammation in atherosclerosis. The TIE2 receptor, located on the luminal surface of the vascular wall, exerts anti-inflammatory effects by modulating the transcriptional activity of Foxo1.235 Notably, TIE1 and TIE2 have opposing roles in regulating atherosclerosis development. Woo et al. reported that TIE1 downregulation in apolipoprotein E-deficient (ApoE−/−) mice reduced atherogenesis by lowering vascular inflammation, indicating that TIE1 has a proinflammatory effect, promoting atherosclerosis development.235,236In advanced atherosclerosis, RTK family members significantly influence plaque stability through multiple mechanisms and are closely associated with clinical outcomes in patients. PDGF has been associated with atherosclerosis progression because it stimulates the migration of smooth muscle cells from the tunica media to the intima-media layer. These cells proliferate and produce matrix molecules, disrupting plaque repair homeostasis.237,238 TAMs are strongly expressed on platelet membranes. After plaque rupture, exposed collagen activates platelet TAM receptors, whereas GAS6-PI3K signaling induces a conformational change in αIIbβ3 integrins, which are involved in platelet activation and thrombosis.23 VEGFR1 also promotes pathological angiogenesis within plaques, increasing bleeding risk.239 Thus, RTK signaling is crucial for endothelial cell function, cholesterol homeostasis, and inflammation. Currently available medications have limited effectiveness in atherosclerosis treatment. RTK-targeted therapies represent novel, effective interventions for this condition; however, further clinical trials and research are warranted to validate their safety and efficacy.Pulmonary arterial hypertensionPulmonary arterial hypertension (PAH) is one of the most challenging-to-treat cardiovascular diseases worldwide and is associated with high mortality and poor prognosis. Although the mechanisms underlying PAH development and progression remain unclear, the condition is pathologically defined by pulmonary microvascular endothelial dysfunction and vascular remodeling. Currently, vasodilation is the main treatment strategy for PAH. The primary clinical approach240 involves using the following agents: endothelin receptor antagonists (ERAs; e.g., macitentan) to block endothelin-1 (ET-1) signaling and inhibit vasoconstriction; phosphodiesterase-5 inhibitors (PDE-5i; e.g., tadalafil) to enhance the nitric oxide–cyclic guanosine monophosphate (NO–cGMP) pathway and improve hemodynamics; and prostacyclin analogs (e.g., treprostinil) to dilate pulmonary vessels by mimicking endogenous prostacyclin.241 However, the therapeutic efficacy of these drugs is suboptimal, with them failing to reverse vascular remodeling.242 In recent years, PAH treatment has shifted from focusing only on vasodilation toward multitarget approaches combining vascular remodeling reversal, anti-inflammatory effects, and metabolic regulation. RTKs may contribute to PAH pathogenesis through the regulation of endothelial homeostasis, smooth muscle cell proliferation, and inflammatory responses; however, their potential as therapeutic targets remains inadequately explored.243VEGFR2 and VEGFR3 can protect against PAH by maintaining endothelial integrity and inhibiting excessive remodeling,244 and VEGFA/VEGFR2 pathway blockade worsens chronic hypoxia-induced pulmonary vasculopathy, leading to occlusive PAH.245 Tuder et al. discovered that VEGFR expression was elevated in patients with severe PAH,246 suggesting that VEGFR may promote angiogenesis; however, its role remains debatable. A recent study provided a possible explanation for the paradoxical role of VEGFR in PAH: VEGFR2Y949F-knockout mice demonstrated fewer PAH symptoms and improvements in inflammatory marker levels. Thus, VEGF-VEGFR2Y949-dependent signaling pathways (including Yes and c-Src, among others) may play a facilitating role, rather than a protective role, in PAH development.247 However, disrupting the entire VEGFR2 signaling process through conditional endothelial VEGFR2 knockout promotes PAH development. Therefore, inhibiting VEGFR2Y949 signaling specifically, instead of completely blocking VEGFR2 signaling, may be a novel treatment strategy for hypoxic PAH.PDGFR is also closely related to vascular homeostasis. In PAH, PDGFR signaling through the PI3K-PLCγ pathway promotes smooth muscle cell proliferation.248 Clinical studies have reported that although the PDGFR inhibitor imatinib improves exercise capacity and pulmonary hemodynamics in patients with PAH, its serious side effects, such as subdural hematoma, limit its clinical use. Researchers are exploring the applicability of inhaled TKIs to reduce systemic toxicity.249,250 Phase II clinical trials have demonstrated the potential of inhaled formulations such as seralutinib and novel RTK inhibitors in treating PAH.251 Moreover, as a multitarget drug, imatinib can inhibit not only PDGFR but also other targets, such as BCR-ABL1 and KIT. This lack of specificity may reduce its therapeutic efficacy and increase the risk of adverse reactions. Therefore, developing more selective TKIs or adopting novel RTK-targeting strategies holds significant potential for PAH treatment. Recently, several innovative therapeutics targeting RTKs, including targeted peptides and antibody-based drugs, have emerged. For instance, intraperitoneal injection of MM-121, an ErbB3-targeting human mAb, was reported to alleviate right ventricular dysfunction and inhibit vascular remodeling in PAH rat models.252 These novel approaches may offer promising new directions for PAH treatment.Dysregulation of EGFR-ErbB family proteins has also been associated with PAH development. Bian et al. reported that ErbB3 is significantly upregulated in the lung tissues of patients with PAH and that it stimulates hypoxia-induced endothelial cell proliferation and exacerbates pulmonary artery remodeling.252 The humanized mAb MM-121 effectively prevents and alleviates PAH by targeting ErbB3. Mechanistically, the EGFR-ErbB pathway exacerbates endothelial dysfunction through interactions with intranuclear Y-box binding protein 1 (YB-1).252 Moreover, upregulation of ErbB3 expression may drive PAH progression through the ErbB3-POSTN-HIF positive feedback loop. EGFR and ErbB2 can regulate POSTN; however, this mechanism is specific to ErbB3, suggesting that ErbB3 is a key target for PAH treatment. In a PAH animal model, the EGFR/ErbB1 inhibitor PKI166 was noted to induce apoptosis in pulmonary artery smooth muscle cells and ameliorate experimental PAH,253 suggesting selective blockade of EGFR signaling to be a viable strategy to reverse PAH.254Moreover, the plasma levels of RET receptor, VEGF ligands, VEGFR-2, FGF, EGFR, MERTK, and HGF have diagnostic value in specifically differentiating PAH from other cardiopulmonary diseases.255,256,257 However, the aforementioned findings are from studies with several limitations; as such, they should be interpreted cautiously. Additional multicenter studies exploring the role and diagnostic value of the aforementioned biomarkers for PAH are warranted. Despite recent advances in the understanding and treatment of PAH, current therapies cannot alleviate the condition. Exploring novel molecular targets for PAH treatment is crucial; however, the application of antiangiogenic drugs targeting RTK, particularly VEGF inhibitors, in clinical PAH treatment should be preceded by exploration of the specific roles of RTKs and angiogenic factors in the development and progression of the condition. Relevant RTK-targeted drugs also require further optimization.Retinal diseasesRetinal diseases, such as wet age-related macular degeneration (AMD), diabetic macular edema (DME), and proliferative diabetic retinopathy (PDR), are characterized by vascular leakage and pathological neoangiogenesis, in which the aberrant activation of RTK signaling pathways is crucial.258 VEGF-VEGFR pathway abnormalities contribute to retinal vascular leakage and neoangiogenesis, making anti-VEGF intravitreal injections, such as ranibizumab and bevacizumab, the first-line treatments for wet AMD and DME.258 However, other signaling pathways (e.g., PDGF and FGF) also participate in angiogenesis, and some patients exhibit an insufficient response or develop resistance to VEGF-targeting monotherapy. This has driven a gradual shift in treatment strategies from single-target VEGF inhibition toward multitarget interventions, leading to the emergence of a series of novel drugs targeting different pathway combinations. During AMD progression, PDGF indirectly enhances vascular leakage control in wet AMD by promoting pericyte migration and improving vascular stability rather than directly participating in the leakage control process. Based on this, a study proposed dual blockade of PDGF and VEGF as a potential strategy to enhance therapeutic efficacy.259 Phase II clinical trials have demonstrated that combining the anti-PDGF drug Fovista with the anti-VEGF drug Lucentis can significantly improve patient vision. However, research on this combination approach was discontinued after three subsequent Phase III trials failed to show superior vision improvement at 12 months compared to monotherapy with anti-VEGF agents. In recent years, bispecific antibodies have emerged as a major breakthrough in multitarget retinal therapy. Faricimab, the first bispecific antibody targeting both Ang-2 and VEGFA, not only inhibits neovascularization but also enhances vascular stability; this allows for extended dosing intervals while improving visual outcomes. A study indicated that Vabysmo dosed every 4 months demonstrated noninferior visual outcomes to those of a 2-month course of aflibercept; furthermore, more than half of the patients could sustain this quarterly dosing interval throughout the 1-year study period.260 Vabysmo was approved by the FDA in January 2022 for DME and wet AMD treatment, becoming the first-ever bispecific antibody drug approved for ophthalmologic conditions. Drugs targeting both VEGF and FGF2 have shown promising prospects. RC28-E, a VEGF/FGF2 dual-target fusion protein, synergistically inhibits neovascularization and inflammatory responses through dual blockade.261 In Phase II clinical trials, intravitreal injection of RC28-E significantly improved best-corrected visual acuity and central foveal thickness in patients with DME. The drug is currently in Phase III clinical development, with concurrent studies underway for both wet AMD and DME.PDR is characterized by abnormal preretinal angiogenesis, which leads to fibrovascular membrane (FVM) formation. This condition poses a significant threat to vision in individuals with diabetes. Anti-VEGF drugs, such as ranibizumab and aflibercept, are the preferred clinical treatment options for PDR as well. Recent proteomics studies revealed that impaired AXL shedding, driven by defective ADAM10 activity, promotes microvascular endothelial activation and FVM formation in PDR, which is significantly suppressed by targeted AXL inhibition.262 Thus, AXL may be a promising novel therapeutic target for PDR. In summary, although anti-VEGF therapy significantly delays the progression of wet AMD, DME, and PDR, it still has considerable limitations. This approach requires frequent intravitreal injections, which can increase the treatment burden and risks such as uveitis and hemorrhage; it can also fail to prevent disease recurrence and irreversible retinal damage occurring through non-VEGF pathways. Therefore, developing novel therapeutic strategies targeting multiple pathways, offering longer efficacy cycles, and ensuring greater safety represents the main challenge in current research on anti-VEGF therapies for retinal disease treatment.In general, RTK signaling abnormalities are significantly implicated in various pathological processes associated with multiple cardiovascular diseases (Table 2). Therefore, targeting RTKs is a novel approach for treating cardiovascular conditions. However, challenges such as mechanistic complexity and insufficient clinical validation must be addressed to achieve precise, effective interventions.Table 2 RTKs in vascular diseasesFull size tableRTKs in neurodegenerative diseasesNeurodegenerative diseases represent a group of disorders characterized by progressive neuronal loss and demyelination.263 Current clinical interventions for these conditions remain largely limited to symptomatic treatment and quality of life improvement, whereas therapies targeting core molecular mechanisms to delay or halt disease progression remain scarce.263 RTKs are critical regulators of nervous system development and function and participate broadly in key physiological processes ranging from neural stem cell maintenance and differentiation to synaptic plasticity.264,265 Accumulating evidence indicates that RTK signaling is essential in the pathological progression of neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). These findings not only deepen the current understanding of the molecular mechanisms underlying these diseases but also provide a theoretical foundation and potential intervention targets for developing targeted strategies directed at the core molecular pathways (Table 3).Table 3 RTKs in neurodegenerative diseasesFull size tableAlzheimer’s diseaseAD, one of the most prevalent and debilitating forms of dementia, is a progressive neurodegenerative disorder, with available treatments largely symptomatic.266 It is pathologically defined by extracellular β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein, and cerebrovascular dysfunction.267,268 In addition to these classic features, dysregulated RTK signaling is increasingly recognized as a critical contributor to AD pathogenesis. Among the various RTK subfamilies, TRKB receptors are particularly significant in AD pathology. Notably, full-length TRKB (TRKB.FL) mediates neuronal protection, whereas upregulation of its truncated isoform (TRKB.T1) impairs this function and accelerates disease progression. An imbalance between the receptor isoforms of TRKB.FL and TRKB.T1 play a crucial role in AD pathology by impairing BDNF signaling.269 BDNF promotes neuronal survival, differentiation, and synaptic function by activating TRKB, and disruption of this pathway contributes to neurodegeneration in AD.270 However, direct administration of BDNF is associated with considerable challenges, including poor BBB permeability and a range of side effects. Given the strong crosstalk and transactivation mechanisms between GPCRs and TRKB, targeting GPCRs to indirectly modulate TRKB signaling may offer a novel approach for overcoming poor BBB permeability.271 Nevertheless, considering existing evidence on BBB disruption in AD, the necessity of this strategy warrants further evaluation.272Accumulating evidence suggests that RTKs contribute to AD through vascular dysfunction. Targeting RTKs to improve BBB function may be a potential therapeutic approach for AD treatment. For instance, TIE2 stabilizes the vascular endothelium and reduces its permeability. In AD models, the combined use of the TIE2 ligand Ang-1 and the anti-inflammatory peptide C16 has been shown to synergistically repair a damaged BBB, effectively suppressing neuroinflammation and vascular leakage and ultimately leading to neuroprotection and functional improvement.273 These compounds may serve as potential therapeutics for AD and warrant further investigation. Recently, Wang et al. employed transcriptomic and machine-learning approaches to reveal that vascular dysfunction in the middle temporal lobe of patients with AD is primarily a result of disrupted communication between endothelial cells and pericytes. An altered VEGFA-VEGFR2 pathway was identified as a core mechanism, with four AD-associated genes (SST, PTPN3, GLS, and TPM3) linked to the VEGF pathway.274 These newly identified targets may have the potential to alleviate AD-related symptoms through VEGF pathway modulation. Aβ oligomers directly bind to and degrade EphB2, suppressing NMDA receptor function and leading to synaptic loss. Notably, reversing this EphB2 depletion can rescue cognitive functions in patients with AD.275 In the related Eph receptor family, aberrant EphA4–EphA1 interactions also promote synaptic degeneration and accelerate disease progression.276 Furthermore, missense mutations in EPHA1 disrupt the membrane localization and phosphorylation of EphA1, resulting in aberrant downstream signaling.277 Targeting these specific disruptions in Eph signaling may be a novel strategy to counteract synaptic failure and cognitive decline in patients with AD.In summary, the pathophysiological processes underlying AD development and progression are closely linked to the dysregulation of multiple RTK signaling pathways (Table 3). The aforementioned findings provide strong theoretical support for developing RTK-targeted therapeutic strategies, providing newer avenues for AD treatment.Parkinson’s diseasePD is a complex neurodegenerative disease characterized by the abnormal accumulation of α-synuclein forming Lewy bodies and selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc).278 Current disease-modifying efforts for PD treatment focus mainly on targeting core pathological mechanisms, including α-synuclein, LRRK2, and GBA1.279 However, exploring nontraditional or emerging therapeutic targets is equally crucial for developing alternative treatments and expanding the therapeutic landscape for PD. RTK family members have attracted growing interest as emerging targets in interventional research for PD treatment.The BDNF-TRKB axis plays a critical role in PD pathogenesis. BDNF is a key survival-supporting factor for dopaminergic neurons, effectively protecting them from degenerative death.280 Studies have observed reduced BDNF levels in PD pathogenesis.281,282 At the receptor level, α-synuclein disrupts normal TRKB activation in dopaminergic neurons through multiple mechanisms, including direct binding to the kinase domain of TRKB and promoting TRKB ubiquitination and degradation.283 Moreover, α-synuclein interferes with the internalization and lipid raft distribution of TRKB, further compromising its function.283 In addition to BDNF, glial cell line-derived neurotrophic factor (GDNF) has been demonstrated to promote mature dopaminergic neuron survival both in vitro and in vivo.284 However, the therapeutic potential of GDNF has long been debated.285 Studies have indicated that in α-synuclein-overexpressing rat models and PD patients with Lewy pathology, α-synuclein accumulation can lead to the downregulation of RET receptor expression, potentially impairing GDNF treatment efficacy.286 Recently, Chmielarz et al. revealed a dual role of the GDNF/RET axis, activating neurotrophic pathways and suppressing misfolded α-synuclein aggregation.287 The authors speculated that after its accumulation exceeds a certain threshold, misfolded α-synuclein may form a vicious cycle with impaired GDNF/RET signaling, thereby accelerating the progression of Lewy pathology. Therefore, initiating GDNF treatment early in the PD course, particularly during the initial stages of Lewy body formation, may exert neuroprotective effects by activating relevant intracellular pathways. Consequently, future research should elucidate the mechanism through which GDNF reduces aggregated α-synuclein accumulation. Concurrently, clinical trials should consider administering GDNF at higher doses or enrolling patients with early-stage PD to better evaluate the targeted therapeutic potential of GDNF.288Amyotrophic lateral sclerosisALS is a fatal neurodegenerative disorder characterized by the degeneration of motor neurons in the brain and spinal cord. This disease leads to progressive weakness and atrophy of the muscles in the limbs, trunk, chest, and abdomen, ultimately resulting in death.289 Recent research on therapeutic strategies targeting RTKs for ALS treatment has revealed several potential targets. Moreover, clinical translation in this field is accelerating, with several candidate drugs (e.g., masitinib and VM202) having advanced to clinical trials, marking a transition of RTK modulation from theoretical validation toward clinical reality.290,291 Masitinib’s efficacy and safety are currently being evaluated in clinical trials; thus, it may shortly become a novel option for ALS treatment. Masitinib primarily exerts its effects by inhibiting KIT and CSF-1R, thereby modulating neuroinflammation via inhibition of mast cell, astrocyte, and microglia activation and survival.292,293Several other RTKs have also been implicated in the complex pathology of ALS. They participate in ALS pathogenesis through multiple mechanisms, mediating neuroprotective effects, as well as regulating neuroinflammation and synaptic stability. Targeting EphA4, an Eph family member, exerts neuroprotective effects by mitigating the toxicity of astrocytes derived from patients with ALS toward motor neurons; this highlights the function of EphA4 in modulating neuron–glia interactions.294 Furthermore, ERBB4, another EGFR family member, has been implicated in ALS progression. Dysfunction of ERBB4 disrupts the neuregulin-ErbB4 pathway, leading to progressive degeneration of both upper and lower motor neurons. This dysfunction can occur due to genetic mutations.295 For instance, the N706D missense variant of ERBB4 impairs autophosphorylation of its TKD, particularly at Tyr1284, thereby hindering ERBB4 receptor activation. This loss-of-function mutation disrupts the neuroprotective regulatory mechanism mediated by the NRG-1/ERBB4 pathway, resulting in interrupted survival signals in motor neurons and eventually contributing to ALS progression.296 Therefore, further elucidating the roles of RTKs such as EphA4 and ERBB4 in ALS pathogenesis and evaluating the potential of targeted therapies may offer future clinical benefits to patients with ALS.RTKs in metabolic disordersDiabetes mellitusDiabetes mellitus is one of the most common endocrine disorders and among the top 10 causes of death worldwide.297 Throughout the 20th century, plant-derived biguanides, sulfonamides, and animal insulin were the only tools available for the clinical treatment of type 2 diabetes mellitus.298 Recent clinical evidence indicates that RTK-targeting strategies may induce remission in patients with type 1 or 2 diabetes mellitus, suggesting their potent role in modulating glucose metabolism.299 In particular, experimental studies in animal and in vitro models have demonstrated the modulatory effects of TKIs on glucose metabolism in both forms of diabetes. A Phase II clinical trial (NCT01781975) demonstrated that 6 weeks of imatinib treatment can preserve β-cell function for 12 months and improve insulin sensitivity.300,301 The exploration of RTK mechanisms in insulin resistance is a valuable frontier for the discovery of novel interventions for diabetes mellitus treatment.VEGFR is linked to pancreatic β-cell damage.302,303 VEGFR2 is upregulated in the inflamed islet vasculature of nonobese diabetic (NOD) mice.304 Inhibiting VEGFR2 can reverse type 1 diabetes mellitus in NOD mice by alleviating insulitis and restoring islet function. Notably, complete VEGF signaling loss is also detrimental. For instance, VEGFA deletion in β-cells impairs islet angiogenesis and endothelial fenestration, leading to defective insulin secretion.305 InsR mediates insulin-related metabolic signaling, and its dysfunction contributes to insulin resistance.306 A recent study found that EphB4 promotes InsR endocytosis and lysosomal degradation, reducing insulin sensitivity in mouse models.307 EphB4 inhibitors, such as NVP-BHG712 and lithocholic acid, were noted to increase insulin-stimulated p-AKT levels and improve insulin resistance in high-fat diet–induced and genetically obese mouse models. Thus, EphB4 inhibition is a potential strategy for treating insulin resistance and type 2 diabetes mellitus.Although EphB4 exemplifies the direct regulation of insulin signaling, a broader array of RTKs modulates systemic insulin resistance through diverse mechanisms. The EGFR inhibitor erlotinib reduces blood glucose levels and improves insulin sensitivity by increasing circulating adiponectin levels.308 PDGF-A overexpression is associated with insulin resistance and increased type 2 diabetes mellitus risk.309,310 Moreover, MET interacts with InsR to form complexes that enhance the hepatic insulin response and IRS2 activation in response to HGF or insulin.311 FGF21 improves insulin sensitivity through FGFR1 and β-Klotho in muscle and adipose tissues and reduces appetite centrally.312 Serum FGF21 levels are positively correlated with insulin resistance in overweight and obese populations,313 potentially reflecting the related compensatory mechanisms or FGF21 resistance. FGF19 primarily enhances glucose tolerance through central mechanisms.314 Intracerebroventricular administration of the FGFR inhibitor PD173074 was noted to induce glucose intolerance in healthy mice.315,316In summary, RTK-targeted therapies represent a novel strategy for intervening in the core pathological mechanisms underlying diabetes mellitus, such as insulin resistance and β-cell dysfunction. However, translating these therapies from cancer treatment to chronic diabetes mellitus management is associated with some key challenges, particularly in terms of long-term safety. Further investigation on the mechanisms through which TKIs (particularly imatinib) alleviate diabetes mellitus, as well as the development of technologies for targeted delivery to key cells, such as pancreatic β-cells or hepatocytes, is essential. These efforts may enable safe clinical translation of RTK-targeted therapies for diabetes mellitus treatment.Nonalcoholic fatty liver diseaseNonalcoholic fatty liver disease (NAFLD), a metabolic liver disorder, is closely associated with obesity and affects approximately 25% of the global adult population. Hepatocellular steatosis constitutes the core pathological alteration in NAFLD. Of all NAFLD cases, 20%–30% progress to nonalcoholic steatohepatitis (NASH), significantly increasing the risk of liver fibrosis, cirrhosis, and HCC.317 Current interventions for NAFLD management depend primarily on lifestyle interventions and symptomatic drug therapies. However, research on the application of RTK inhibitors or RTK antibodies in NAFLD treatment remains in preclinical stages. Evidence suggests that some RTKs contribute to NAFLD progression. EGFR is hyperphosphorylated in high-fat diet–induced NAFLD mouse models, indicating EGFR pathway activation.318 Pharmacologic inhibition of EGFR, such as with canertinib, has been shown to effectively prevent steatosis, liver injury, and fibrosis in murine models of NAFLD.318 In vitro findings indicate that VEGF stimulates brown preadipocyte proliferation. The VEGFR2-targeting antibody DC101 was reported to successfully resolve high-fat diet–induced steatosis and NASH in vivo.319 Patients with NASH demonstrate increased signaling of AXL, a TAM family protein, which promotes fibrosis in HSCs and inflammation in Kupffer cells.320,321,322 However, AXL inhibition can delay weight gain in mice.321 Moreover, bemcentinib can block AXL signaling, activate MERTK and alleviate experimental NASH.322 In the PDGF family, CSF1-CSF1R signaling drives lipotoxicity by upregulating lipodystrophy-related genes and Kupffer cell infiltration.323 Similarly, PDGFRβ activation suppresses matrix degradation via the PI3K-AKT/RAS-MAPK pathways, promoting fibrosis.324Specific RTK signaling pathways can suppress NAFLD pathogenesis and progression. Several studies have indicated that NRG4 signaling via the RTKs ERBB4 and ERBB3 inhibits hepatic lipogenesis.325,326,327 Moreover, HGF treatment can reverse steatosis by promoting lipid secretion.328 Furthermore, HGF overexpression has been noted to protect against high-fat diet–induced fatty liver through activation of microsomal triglyceride transfer protein and apolipoprotein B in mice.329 Finally, the RET ligand GDF15 has been reported to activate the GFRAL-RET signaling complex in the hindbrain to suppress appetite and regulate body weight.330 In summary, RTK-targeted therapies hold potential for NAFLD treatment by offering an integrated treatment strategy that improves metabolic abnormalities, inhibits inflammation and fibrosis, and promotes tissue repair simultaneously. Therefore, precisely defining the specific roles of key RTKs in various cell types, such as hepatocytes, HSCs, and immune cells, as well as their integrated biological functions, throughout the dynamic course of NAFLD is essential.Table 4 summarizes the roles of different RTKs in various metabolic disorders, highlighting their diverse mechanisms and complex functions in metabolism. Despite the promising prospects, the clinical translation of RTK-targeted therapies remains challenging. The dynamic progression of metabolic disorders necessitates precise tailoring of interventional strategies to different stages of each disorder.Table 4 RTKs in metabolic disordersFull size tableRTKs in autoimmune diseasesAutoimmune diseases are primarily characterized by the immune system’s sustained aberrant response to the host’s normal components.331,332 Advancements in molecular biology, immunology, genetics and clinical medicine have enabled elucidation of the mechanisms underlying some autoimmune diseases. However, their primary drivers and subsequent pathological progression remain unclear.333 Nevertheless, accumulating evidence indicates that RTK signaling may play a critical regulatory role in the pathogenesis of autoimmune diseases (Table 5). Notably, although the pathological roles of some RTKs in rheumatoid arthritis (RA) pathogenesis have been preliminarily elucidated, relevant research across the entire spectrum of autoimmune diseases remains in its early stages. The precise mechanisms of action of many RTKs and their clinical value as therapeutic targets for autoimmune disease treatment require further investigation.Table 5 RTKs in autoimmune diseasesFull size tableRheumatoid arthritisRA is characterized by progressive systemic inflammation and chronic joint injury.334 TAM receptors, as key immunomodulatory factors, play a key role in RA. In the pathological process of RA, AXL and MERTK showed protective effects.335 GAS6 and AXL levels are significantly decreased in the peripheral blood of patients with RA,336 and the mechanism underlying this observation may be related to AXL inhibition caused by miR-34a overexpression in CD1c+ dendritic cells (DCs).337 Knee joints of MERTK-deficient mice show more severe cartilage proteoglycan depletion and bone erosion. Nevertheless, PROS1 overexpression reverses these pathological changes.338 In contrast, TYRO3 leads to pro-RA pathological progression: TYRO3 knockout was noted to significantly inhibit synovial proliferation and bone destruction processes in an arthritis model.339 In mice deficient in the kinase domain of TYRO3, multifaceted protective effects against RA, including decreases in inflammatory cytokine secretion and the migratory and invasive capacity of RA fibroblast-like synoviocytes (RA-FLS), along with inhibition of RA-FLS-mediated differentiation of pathogenic helper T-cell subsets, were observed.340 Clinical studies further confirmed that in patients with RA, TYRO3 expression on CD14+CD16+ monocytes (osteoclast precursors) is significantly positively correlated with disease activity and that anti-TYRO3 antibody effectively blocks GAS6-induced osteoclast differentiation.341PDGFR is essential for maintaining the erosive phenotype of RA synoviocytes. In addition, RA synoviocytes induce PDGF-B production by autocrine TGF-β, which in turn promotes invadosome formation.342 Laragione et al. identified Huntingtin protein-interacting protein 1 (HIP1) as a key factor for stable RTK expression on FLS surfaces. HIP1 may mediate RAC1 activation, ultimately enhancing PDGF-induced FLS invasion via regulation of the membrane expression and downstream signaling of PDGFR.343 Imatinib mesylate reduces RA synoviocyte activation by interfering with PDGFR signaling.344 In an experimental arthritis model, this drug demonstrated significant inhibition of articular bone destruction.345 Moreover, complete remission has been reported in some RA patients treated with imatinib.346,347,348 However, the relatively high toxicity profile of imatinib limits its clinical use.349 Therefore, precise identification of specific RTK subtypes involved in joint erosion is essential for developing efficient, safe targeted treatment regimens.Systemic sclerosisSystemic sclerosis (SSc) is a systemic autoimmune disorder pathologically defined by cutaneous thickening and fibrosis. RTKs may have regulatory roles in SSc pathogenesis. EphB2 is a key mediator of dermal fibrosis in SSc, and silencing it in human dermal fibroblasts can sufficiently inhibit TGF-β-induced differentiation of fibroblasts to myofibroblasts.350 This indicates the potential of EphB2 as a target for SSc treatment. Compared with healthy controls, patients with SSc have elevated serum and skin Ang-2 levels, and serum Ang-2 levels are correlated with clinical disease parameters such as skin involvement.351,352 Mechanistic studies have demonstrated that Ang-2 drives inflammatory activation of monocytes in patients with SSc. In contrast, TIE2 inhibition significantly attenuates cytokine secretion in serum-stimulated monocytes from patients with SSc.352 Thus, Ang-2 and TIE2 are potential biomarkers and therapeutic targets for SSc.Behçet’s diseaseBehçet’s disease (BD), a chronic relapsing immune disorder, is clinically characterized by oral and genital ulcers, erythema nodosum, gastrointestinal lesions, arthropathy, recurrent vasculitis, and neurological abnormalities. In patients with BD, circulating GAS6 levels are significantly decreased, accompanied by enhanced AXL receptor shedding, which manifests as elevated levels of serum soluble AXL (sAXL).353 Given the established role of this axis in promoting efferocytosis and dampening innate immune responses, such deficiencies may lead to the accumulation of apoptotic debris and the failure of inflammation resolution, thereby perpetuating the autoimmune phenotype.354 Therefore, GAS6-TAM signaling may contribute to the pathological progression of BD. Additional functional and mechanistic studies are required to delineate the precise regulatory network underlying BD pathogenesis.Systemic lupus erythematosusSystemic lupus erythematosus (SLE), an autoimmune disease characterized by multiorgan involvement, has a pathogenesis closely related to dysfunctional immune regulation.355,356 TAM receptors may be involved in the pathological process of SLE development and progression. Plasma soluble TAM receptors and ligands can be used as potential biomarkers for assessing SLE progression and prognosis.354,357 Notably, in lupus nephritis secondary to SLE, plasma sMERTK, sAXL, and GAS6 levels are significantly positively correlated with renal disease activity and histopathological damage severity.358RTKs in fibrotic diseasesFibrosis is a pathological outcome resulting from the repair response after tissue or organ damage. It is often caused by excessive accumulation of ECM components, such as collagen and fibronectin.359 RTKs are involved in fibrosis regulation within various tissues and organs (Table 6). Currently, the only RTK-targeting molecule with proven effectiveness against a fibrotic disease is nintedanib for idiopathic pulmonary fibrosis (IPF). The application of RTK-targeting strategies to fibrotic diseases, such as IPF, is largely in the exploratory research phase.Table 6 RTKs in fibrotic diseasesFull size tableHepatic fibrosisHSCs are the key cells responsible for ECM synthesis, and their activation is critical for liver fibrosis development.360,361 Bárcena et al. observed that their animal liver injury model demonstrated an increase in the GAS6 level, which led to HSC and myofibroblast activation. In chronic liver diseases, the GAS6-AXL pathway is activated, and targeting this pathway reduces fibrosis through HSC inactivation.362 Moreover, AXL has several roles in liver fibrosis related to steatohepatitis. Patients with NASH demonstrate an increase in AXL signaling, promoting HSC fibrosis and Kupffer cell inflammation.322 AXL also promotes steatohepatitis related to metabolic dysfunction by activating HSCs and macrophages. As such, targeting AXL can promote fibrosis regression.363 In summary, GAS6 and sAXL are proposed biomarkers for chronic liver diseases, with high detection accuracy for significant fibrosis and cirrhosis.363 These findings contribute to the current understanding of chronic liver diseases and different steatohepatitis types. Further research clarifying the potential mechanisms and translational potential of GAS6 and AXL in various liver diseases is warranted.Other RTKs are also involved in liver fibrosis. For instance, TRKB can inhibit liver fibrosis by suppressing TGF-β-SMAD pathway activation.24 In a model of fatty liver disease related to metabolic dysfunction, EGFR deletion was noted to enhance hepatocyte fibrosis.364 Furthermore, MSP-RON signaling can promote liver fibrosis progression through TGF-β-related pathways, whereas the small-molecule RON inhibitor BMS-777607 can significantly reverse CCl4-induced experimental liver fibrosis.190 These results indicate that RTKs from several families can promote liver fibrosis through different mechanisms. An in-depth understanding of the molecular mechanisms through which RTKs promote liver fibrosis can facilitate liver fibrosis inhibition from multiple perspectives, such as hepatocyte injury, liver inflammation, and HSC activation, laying a foundation for the development of effective clinical treatment methods.Pulmonary fibrosisPulmonary fibrosis development is related to pathological processes such as fibroblast activation, EMT, and the inflammatory response.365,366 Various RTKs have been confirmed to be involved in pulmonary fibrosis processes underlying diseases such as lung injury and IPF. DDRs play a substantial role in fibrosis progression in IPF. For instance, DDR1 upregulation can be observed in bronchial epithelial cells of patients with IPF. DDR1 knockdown can significantly weaken pulmonary fibrosis in lung injury models. Therefore, DDR1 expression is a prerequisite for pulmonary fibrosis development.367 DDR2 can regulate apoptosis in IPF fibroblasts by activating the PI3K-AKT pathway368 and promote lung myofibroblast activation induced by TGF-β or type I collagen.369Other RTKs, such as TRK, EPH, TIE, and VEGFR, are involved in the pulmonary fibrosis process related to diseases such as lung injury and IPF. Activation of the BDNF/TRKB axis promotes pulmonary fibrosis development through activation of the MAPK-dependent TWIST-SNAIL axis and facilitation of EMT,370 as well as through the promotion of ECM deposition.371 Hohmann et al. used ifabotuzumab to target EphA3+ cells in humanized immunodeficient mice, and it considerably alleviated pulmonary fibrosis.372 Ou et al. reported that increased VEGF-VEGFR expression is associated with an elevated pulmonary fibrosis score and that VEGFR2 inhibitors can alleviate tissue fibrous hyperplasia and collagen deposition.373 Nintedanib, a small-molecule RTK inhibitor that targets molecules, including FGFR, VEGFR and PDGFR, can reduce the decline in lung function and acute deterioration in patients with IPF374; it has thus been approved for the treatment of IPF since 2014. In general, the aforementioned RTKs have potential as therapeutic targets for pulmonary fibrosis.AXL also plays a role in IPF development and progression; however, its functional role remains controversial. Espindola et al. noted elevated AXL levels in lung samples and fibroblasts of patients with IPF and showed that GAS6/TAM receptor activity contributes to pulmonary fibroblast activation.375 However, Lee YJ et al. indicated the potential role of GAS6/AXL in inhibiting fibroblast activation and ultimately preventing pulmonary fibrosis development.376 Therefore, relevant research using different pulmonary fibrosis models is needed to obtain a complete understanding of the different roles of GAS6/AXL in pulmonary fibrosis processes.AXL is also involved in environment-related pulmonary fibrosis development. In pulmonary fibrosis induced by indoor exposure to volatile organic compounds, pulmonary microvascular endothelial cells secrete GAS6 after PANapoptosis, which binds to AXL and activates fibroblasts.377 Lung fibroblasts exposed to tobacco smoke demonstrate an increase in AXL expression and enhanced invasive activity; nevertheless, AXL inhibition can suppress the invasive phenotype of these fibroblasts. Thus, AXL is a potential marker of tobacco-related pulmonary fibrosis, and targeting the AXL pathway is a potential strategy for its treatment.378Cardiac fibrosisCardiac fibrosis can occur in various heart diseases, such as coronary heart disease and heart failure. It is related to the induced differentiation of myofibroblasts and deposition of structural proteins (e.g., collagen).379,380 AXL, DDR, and ROR are implicated in cardiac fibrosis. Zhao YF et al. found that mice with GAS6 deficiency had less cardiac hypertrophy and fibrosis after aortic girdling; however, GAS6 overexpression exacerbated cardiac fibrosis.381 DDR2 knockout alleviates angiotensin-induced cardiac fibrosis,382 and DDR2 has a role in vascular fibrosis and diabetic cardiomyopathy-related cardiac fibrosis.383 Chavkin et al. confirmed in a surgical model of transverse aortic coarctation that ROR can induce myofibroblast differentiation, thereby promoting cardiac fibrosis,384 highlighting the key role of ROR1/2 in controlling the inflammatory phenotype of fibroblasts in the early stages of cardiac remodeling. Because of various factors involved in cardiac fibrosis pathogenesis, extremely few therapies are available for this condition. Therefore, in general, RTK targeting represents a potential approach for cardiac fibrosis treatment.Renal fibrosisEph and DDR can promote renal fibrosis and inflammatory responses. Specifically, EphB2 expression is upregulated in fibrotic renal tissues, and its targeted knockout effectively reduces renal tubular fibrosis and inflammation.385 Furthermore, DDR1 activation drives renal injury by promoting MCP-1 and TGF-β production.386 DDR1 deficiency has been observed to significantly weaken glomerular fibrosis and inflammation in a hypertensive nephropathy model.387 Thus, the aforementioned RTKs may be used as targets for renal inflammation and fibrosis treatment.Skin fibrosisVarious RTKs play a role in diseases related to skin fibrosis. Keloid fibroblasts strongly express IGF1R, and the invasive activity of these cells is significantly increased and can be inhibited by neutralizing antibodies against IGF1R. Thus, IGF1R is involved in keloid pathogenesis through enhancement of fibroblast invasive activity.388In summary, RTKs from various subfamilies are involved in the fibrotic processes of various organs via different underlying mechanisms (Table 6). However, fibrosis progression is a multifactorial, multistage, and complex process that may not be adequately addressed by targeting a single RTK. The successful application of nintedanib, a multitarget RTK inhibitor, further validates this point.389 Moreover, exploring combination therapy strategies integrating RTK-targeted treatments with anti-inflammatory and immune modulation approaches may be a feasible path to achieve more significant outcomes during fibrosis treatment.RTKs in infectious diseasesThe roles of RTKs as key coreceptors and regulators of pathogenic infections have garnered increasing attention recently. RTKs facilitate host cell invasion through direct interactions with viral spike proteins, mediating viral internalization or membrane fusion to promote viral entry into host cells.390 Repurposing numerous FDA-approved kinase inhibitors for antiviral therapy is a promising and time-efficient strategy. Compared with direct-acting antivirals, kinase inhibitors are less prone to resistance and more capable of targeting diverse viral genotypes or serotypes, thus having more broad-spectrum actions.391 However, current research on RTKs for antiviral therapy is primarily in the preclinical stage, and the specific mechanisms of relevant RTKs and their potential for translational applications warrant further in-depth investigation.Respiratory virus infectionsRTKs play crucial roles in mediating the replication of respiratory viruses. Influenza virus infection can induce lipid raft aggregation through multivalent virus binding, in turn activating several RTKs, including EGFR and TRKA, and thus facilitating efficient viral internalization.392,393 In addition to promoting viral entry, EGFR activation can suppress airway epithelial interferon λ production and antiviral responses, further enhancing viral replication.394 In a TRKAF592A knock-in mouse model, TRKA was noted to be activated during infection, with its primary function occurring during the replication phase after viral entry. Moreover, TRKA exacerbated airway inflammation and pulmonary lesions by inducing the expression of proinflammatory cytokines and chemokines. Furthermore, TRKA kinase activity inhibition by using the small-molecule 1NMPP1 was noted to protect mice from lethal infection with the A/PR8 strain.393 Influenza virus may also enter cells via the PDGFRβ/GM3 pathway; Ki8751, a specific RTK inhibitor, can block this endocytosis.Coronaviruses can infect both humans and animals, and some human coronaviruses can cause severe-to-fatal respiratory tract infections. Shin et al. discovered that SARS-CoV-2 infection involves abnormal activation of EGFR signaling. The virus promotes the translocation of EGFR to the outer mitochondrial membrane, enhancing oxidative phosphorylation and facilitating viral transmission.395 Treatment with EGFR inhibitors (e.g., vandetanib) was observed to significantly reduce viral replication and shedding and effectively lower viral load in the lung tissue of mouse models, indicating the potential of EGFR as a host target against SARS-CoV-2 infection.395 AXL has also been implicated in SARS-CoV-2 infection mechanisms because it interacts with the N-terminal domain of the viral spike protein to facilitate infection of respiratory epithelial cells.396 Because AXL knockdown can attenuate the infectivity of various viral variants, it is a potential disease progression biomarker and therapeutic target in respiratory viral infections. In summary, RTKs such as EGFR, TRKA, and AXL are potential treatment targets for combating severe respiratory viral infection.Hepatitis C virus infectionHepatitis C virus (HCV), a major cause of cirrhosis and hepatocellular carcinoma, primarily enters hepatocytes through hepatic sinusoidal endothelial cells. HCV entry is a complex, multistep process dependent on multiple host cell factors that facilitate viral uptake by hepatocytes. During this process, cell receptors, particularly RTKs, act as essential cofactors. Moreover, HCV exploits RTK signaling pathways to suppress the antiviral response mediated by type I interferons and thus facilitates viral evasion of host innate immune defenses. The RTKs EphA2 and EGFR are crucial cofactors for HCV viral entry.397 EGFR and EphA2 facilitate HCV entry by modulating the CD81-claudin-1 interaction and promoting viral glycoprotein-mediated membrane fusion.398 Moreover, HCV infection induces core fucosylation of EGFR, promoting TRIM40-mediated ubiquitination and degradation of RIG-I. This process ultimately suppresses type I interferon-mediated antiviral responses, facilitating viral evasion of host immunity.399 The EGFR inhibitor erlotinib has been noted to exhibit antiviral activity by affecting the aforementioned mechanism in vitro—at half-maximal inhibitory concentrations of 0.45 and 0.53 μM against HCV entry and infection, respectively. In uPA-SCID chimeric mice with established HCV infection, erlotinib treatment reduced steady-state HCV RNA levels by >90% and considerably impeded disease progression.397 A subsequent Phase Ib randomized controlled trial established the safety profile of erlotinib and confirmed its favorable antiviral efficacy in patients with chronic hepatitis C.400 Therefore, targeting the EphA2/EGFR pathway represents a novel anti-HCV treatment strategy, providing a basis for further clinical development of combined therapies.Filovirus infectionsFiloviruses, including Ebola and Marburg viruses, cause fatal hemorrhagic fever by interacting with host cell-surface receptors via their envelope glycoproteins. Of the host cell-surface receptors, TAM receptor family members are key mediators of entry of these viruses into host cells. Rather than binding directly to TAM receptors, viral glycoproteins recruit bridging ligand proteins such as GAS6. Mechanistically, one end of GAS6 recognizes viral particles, whereas the other activates TAM receptors, triggering clathrin-mediated endocytosis and thus facilitating viral entry into host cells.390,401 To facilitate infection, filoviruses can exploit multiple RTK signaling pathways in addition to the TAM receptor pathway. For instance, viruses can activate EGFR, MET, and InsR-IGF1R, triggering downstream signaling cascades that synergistically enhance viral entry. SU11274 (MET inhibitor) and NVP-ADW742 (IGF1R inhibitor) block viral translocation to the NPC1 receptor. Gefitinib (EGFR inhibitor) disrupts membrane fusion by altering the NPC1-positive compartment phenotype. In general, RTK signaling has critical roles in regulating filovirus internalization and subsequent entry steps402; thus, RTK inhibitors may be applicable as broad-spectrum antifiloviral agents.In summary, RTKs are pivotal in various viral infection processes. They function not only as essential coreceptors for viral entry into host cells but also as regulators of immune evasion and viral replication. Targeting RTK signaling pathways has broad-spectrum antiviral potential, with certain inhibitors demonstrating promising results in preclinical studies and early clinical trials. This offers a significant direction for developing novel antiviral therapeutic strategies. However, the role of host signaling pathways in viral replication and disease severity may vary depending on the virus and cell type. As such, in-depth evaluation is warranted before the development of RTK-based antiviral therapeutic agents to combat various current and emerging viral diseases.Therapeutic targeting of RTKsRTKs and their signaling pathways are crucial for normal biological functions. However, their dysregulation can contribute to the development of various diseases, including cancer and other noncancerous conditions, posing a significant public health risk. Therefore, targeting RTKs and their pathways is critical for the treatment of relevant diseases. Currently, RTK-targeted therapeutic modalities are typically employed in cancer treatment. Moreover, certain drugs, such as nintedanib for IPF, have also been approved for noncancerous conditions. In this section, we summarize the current RTK-targeted therapeutics, including small-molecule RTK inhibitors, therapeutic antibodies, ADCs, and other treatment modalities such as nanoparticles (NPs) and drug combinations (Fig. 7).Fig. 7Full size imageTherapeutic strategies targeting RTKs. Therapeutic strategies targeting RTKs are multimodal, including receptor inhibition, ligand blockade, genetic modulation, and engineered cellular interventions. CAR-T chimeric antigen receptor T cell, ADC antibody‒drug conjugate, PROTAC proteolysis-targeting chimera, LYTAC lysosome-targeting chimera, RNAi RNA interference, siRNA small interfering RNA, miRNA microRNA, sgRNA single-guide RNA, RISC RNA-induced silencing complex, PAM protospacer adjacent motif, ATP adenosine triphosphate. Image created with BioRender (https://biorender.com/)Small-molecule RTK inhibitorsSmall-molecule RTK inhibitors, representing the most classic RTK-targeted therapeutics, primarily target the intracellular domains of TKs by competitively obstructing their ATP-binding sites.13 Over the past decades, RTK inhibitors have demonstrated effectiveness in treating various cancers. Some of them have been employed for the standard treatment of specific diseases. For instance, osimertinib selectively targets EGFR mutations without considerably affecting wild-type EGFR, and it is currently used as the main first-line targeted therapeutic for most lung cancers with EGFR mutations.403 Fruquintinib and nintedanib, both of which target VEGFR, have been used in subsequent-line treatment settings for colorectal cancer and NSCLC, respectively.404Pharmacokinetic properties such as metabolic stability and oral bioavailability are critical determinants of the clinical effectiveness of small-molecule inhibitors. Although strategic optimization can efficaciously enhance these parameters to ensure adequate drug exposure in vivo, resistance mechanisms and adverse effects remain major obstacles to the long-term clinical utility of these inhibitors. Resistance to RTK inhibitors can be divided based on the underlying mechanisms into primary and acquired resistance. Tumor heterogeneity is a main cause of primary drug resistance. Acquired resistance mechanisms include in-target resistance, such as mutations in the RTK kinase domain that prevent drug binding, and off-target resistance, such as alterations in downstream pathway components, which bypass the original TKI target.405 Indeed, as comprehensively discussed by Wu et al., acquired TKI resistance is a highly dynamic and multifactorial phenomenon.406 Beyond target mutations and bypass signaling, this complex network is also significantly driven by profound changes in the tumor microenvironment and the dysregulation of drug efflux and uptake mechanisms. Overcoming these formidable barriers necessitates innovative tackling strategies. Adverse reactions can result from on-target reactions and off-target toxicity. For instance, VEGFR-targeting TKI inhibits the angiogenesis pathway, possibly leading to surgical delay and wound-healing complications.208 Regarding off-target toxicity, RTK inhibitors have notable cardiotoxicity, with several of them causing irreversible heart dysfunction.407 When drug resistance or overly strong adverse reactions occur for various reasons, RTK inhibitors need to be supplemented with or replaced by other treatment methods. Therefore, the development of newer therapeutic strategies that may resolve these limitations (e.g., drug combinations) is warranted.406At present, the development of small-molecule RTK inhibitors is an active research field, with promising research avenues such as multitarget compounds, allosteric inhibitors, and covalent binders. Most clinically approved TKIs are ATP-competitive, including type I (binding the active DFG-in conformation) or type II (binding the inactive DFG-out conformation) inhibitors. Because the ATP-binding pockets in RTK domains are highly conserved, ATP-competitive TKIs can concomitantly inhibit several kinases. Therefore, multitarget TKIs, such as sorafenib and pazopanib, have emerged. The anticancer effects of these drugs may be attributable to the combined actions of multiple signaling molecules. For instance, lenvatinib can exert a powerful antitumor effect by inhibiting the FGF and VEGF signaling pathways, further consolidating the role of RTK inhibitors in the first-line treatment of advanced HCC.408 However, this characteristic also leads TKIs to demonstrate poor selectivity, unsatisfactory effects on given targets, and short durations of action409; it also makes the development of highly selective TKIs challenging. However, allosteric TKIs (type III or type IV kinase inhibitors) that bind to allosteric sites outside the conserved ATP-binding pocket may resolve this issue. For instance, EAI045, a type III allosteric kinase inhibitor, binds to an allosteric site created by the displacement of the C-helix in the inactive EGFR conformation. By avoiding the ATP-binding pocket, EAI045 confers enhanced selectivity and demonstrates effectiveness against ATP-site mutants such as L858R/T790M.410 Covalent binders form covalent bonds with kinase sites, thereby irreversibly altering target activity.34 Overcoming mutation-induced drug resistance, such as the T790M mutation in EGFR, is challenging. However, next-generation RTK inhibitors that covalently bind to ATP-binding sites can selectively target sensitizing mutations and demonstrate improved safety.411 These innovative approaches are increasingly recognized as essential paradigms for tackling complex resistance networks.406Table 7 summarizes all FDA-approved RTK inhibitors (as of April, 2026), along with their targets, approval dates, and therapeutic uses. The FDA has approved 54 small-molecule RTK inhibitors targeting multiple RTK subfamilies. Of them, some can target only one RTK, whereas others can target two or multiple RTKs. These RTK inhibitors are used for treating various cancers, including NSCLC, breast cancer, CRC, and liver cancer, as well as noncancerous conditions such as myeloproliferative diseases and IPF. Numerous RTK inhibitors are also being assessed in clinical trials.Table 7 FDA-approved small-molecule RTK inhibitorsFull size tableRTK antibodiesIn the past 30 years, therapeutic antibody use has gradually become a classical targeted therapy approach. mAbs can bind specifically to extracellular target antigens, inducing cytotoxicity and promoting innate immune responses.412 Therapeutic mAbs mainly bind to the extracellular domains of RTKs with high specificity. This enhances the efficacy and safety of the treatment and the ability of protein–protein interaction inhibition, a property often unattainable by small-molecule drugs.413 However, because cellular signaling networks are inherently redundant and adaptable, the blockade of a single pathway often drives resistance through the activation of compensatory bypass pathways. For instance, activation of ErbB3 or MET signaling aids cancer cells in developing resistance to cetuximab, which targets EGFR.74,414 Consequently, bispecific antibodies (bsAbs) have been developed.These bsAbs can be used to overcome the limitations related to tumor heterogeneity to some extent; they may even demonstrate better clinical efficacy than monospecific antibodies.415 The two targets of a bsAb can be two components of one RTK416 or two RTKs from different families or from the same family,417 or one RTK and another antigen (e.g., an immune checkpoint).418 Many protein engineering strategies for bsAb construction, such as Knobs-into-holes419 and CrossMab,420 have been developed and applied. However, blocking more targets may be related to higher adverse reaction risks. Similar to RTK inhibitors, RTK-targeting bsAbs have significant cardiovascular adverse effects. These adverse reactions include venous thrombotic diseases, abnormal blood pressure, and arrhythmia. The mechanism suggested to underlie these reactions is on-target toxicity resulting from the inhibition of RTK signaling pathways, such as the EGFR and HER2 pathways, which are involved in maintaining normal cardiovascular function.407 In addition, bsAb target selection, design, and construction are associated with limitations.421 This has led to further optimization of bsAb design to improve efficacy and safety, along with combining bsAbs with other therapies or producing antibody derivatives.As of April, 2026, the FDA has approved 11 RTK antibodies. Teprotumumab has been approved for thyroid eye disease treatment, whereas the remaining 10 have been approved for cancer treatment. Of these antibodies, amivantamab and zenocutuzumab are bispecific mAbs, whereas the others are mAbs targeting a single epitope. Table 8 lists the names, targets, FDA approval dates, and therapeutic indications of these antibodies.Table 8 FDA-approved RTK antibodiesFull size tableADCsAntibody–drug conjugates (ADCs), comprising a tumor-targeting antibody connected to a cytotoxic payload via a complex chemical linkage, are designed to combine precise targeting with potent efficacy. After ADCs bind to their target antigens on cancer cells, the conjugates are internalized, whereby they release their cytotoxic payload, inducing apoptosis through DNA or microtubule targeting.422 Compared with RTK inhibitors and specific antibodies, ADCs have some unique advantages. ADCs can bridge the gap between mAbs and cytotoxic drugs, prolonging the therapeutic window.423 Coupling drugs with large hydrophilic antibodies restricts the antigen-independent uptake of cytotoxic payloads in antigen-negative cells, enhancing therapeutic indexes.424Of all FDA-approved ADCs, ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) target RTK via HER2. T-DM1 is composed of trastuzumab, a humanized mAb targeting HER2, conjugated to DM1 via a noncleavable linker at a drug-to-antibody ratio (DAR) of 3.5.425 Considering the encouraging results of the Phase III EMILIA trial, T-DM1 was approved by the FDA in February 2013.426 T-DXd is composed of trastuzumab connected to a topoisomerase I-inhibiting exatecan derivative via a cleavable tetrapeptide-based linker at a DAR of 8.427 Based on its high efficacy in the Phase II DESTINY-Breast01 trial, the FDA approved T-DXd in December 2019.428 Despite the encouraging results in the aforementioned clinical trials, ADCs demonstrate drug resistance and toxicity. For instance, the common adverse events of T-DM1 treatment include thrombocytopenia and increased aspartate transaminase and alanine transaminase levels.429 To address these issues, research focused on identifying more promising candidate antigens430 and selecting more appropriate coupling strategies431 for the development of ADCs is underway.In preclinical studies, ADCs targeting other RTK subfamilies have also been effective in the treatment of various cancers, laying a foundation for subsequent clinical research; these ADCs include TR1801-ADC targeting MET,432 ADCT-601 targeting AXL,433 and H-Zt/g4-MMAE434 and H5B14-MMAE435 targeting RON. More than 50 ADCs targeting various RTKs (e.g., EGFR, HER2, HER3, c-MET, AXL, ROR1/2, EphA3/5, FGFR3, and IGF1R) are currently under clinical trials.436 Furthermore, dual-targeting ADCs are an effective strategy against tumor heterogeneity. For instance, the killing effect of PCMdt-MMAE targeting MET and RON on tumor cells and its inhibitory effect on tumor growth have been confirmed in preclinical studies.417 Selecting the appropriate dual targets and developing more dual-targeting ADCs may represent a future direction for ADC development.Drug combinationsCompared with monotherapy, rationale-based drug combinations can reduce drug resistance to a certain extent and improve therapeutic effects through varied mechanisms of action.31,437Different TKIs are commonly combined with other TKIs, mAbs, or chemotherapeutic drugs.Angiogenesis inhibitors are frequently integrated into these combination strategies; they can normalize the tumor vasculature and improve tumor perfusion, antitumor drug uptake, and cancer therapy efficacy.438 Perioperative gefitinib enhances survival in patients with EGFR-mutated NSCLC compared with conventional chemotherapy; however, resistance typically occurs within 8–12 months.31 In preclinical models of EGFR-mutant NSCLC, integrating an angiogenesis inhibitor into EGFR-TKI therapy enhanced prognosis by reversing primary or acquired EGFR-TKI resistance.437Immunotherapy combined with RTK inhibitors is also a promising approach that has been widely studied in preclinical and clinical trials. The introduction of VEGFR-TKIs and immunotherapies (IOs) has substantially altered the treatment landscape for kidney cancer, and doublet combination immunotherapy (IO/IO or IO/VEGFR-TKI) is now considered the standard frontline treatment for advanced renal cell carcinoma (RCC).439 Although immune checkpoint inhibitor (ICI) monotherapy cannot effectively reduce the size of primary tumors,440,441 ICIs combined with VEGFR-TKIs may be beneficial. The Phase II NeoAvAx trial revealed that combining avelumab, a programmed death ligand 1 (PD-L1) inhibitor, with axitinib442 may be feasible and effective. Combinations of programmed cell death protein 1 (PD-1) inhibitors have demonstrated notable benefits in various clinical trials.443 Collectively, these clinical trials have confirmed that combinations of immunotherapy with RTK inhibitors exhibit promising anticancer activity but with a manageable toxicity profile. Several TKI-ICI combination therapies, however, have been ineffective. Clinical studies have indicated that ICI monotherapy affords limited benefits to NSCLC patients after EGFR-TKI failure.444 The effectiveness of combining ICIs with chemotherapy for EGFR-TKI-resistant NSCLC remains debated.445 Cancer patient populations tend to demonstrate significant heterogeneity. Thus, to ensure substantial treatment benefits and efficiency, efficacy biomarker identification must include effective patient screening.Nanodrug delivery systemIn nanodrug delivery systems (NDDSs), nanoscale structures and particles, characterized by a high surface-to-volume ratio and adaptable structure, are used for drug delivery.446 For instance, liposomes, the most extensively studied nanomaterials, are closed spherical vesicles comprising a lipid bilayer encapsulating an aqueous phase, where drugs can be stored. Liposomes can merge with cells, undergo endocytosis, and deliver drugs intracellularly. Incorporating antibodies targeting tumor-specific antigens (e.g., RTK-targeting mAbs) into liposome design to ensure active targeting can effectively improve delivery efficiency.447 Polymer NPs (PNPs), also widely studied drug nanocapsules, are composed of a polymeric backbone of a biodegradable monomer and functional moieties for active targeting intercalated into their structure. PNPs exhibit high thermodynamic stability, tunable particle size, and modifiable surface properties that influence endothelial permeability and systemic clearance.446Research on improving RTK-targeting NP design is ongoing, and the anticancer effects of many RTK-targeting NPs have been confirmed in preclinical studies. For instance, Juul et al. designed a liposome containing the chemotherapeutic drug oxaliplatin with trastuzumab (which targets HER2) and a polyethylene glycol (PEG) layer on its surface. Trastuzumab can promote liposome internalization by cancer cells. After liposome accumulation in the tumor, MMPs inside and outside the tumor cell cleave their PEG layer, resulting in the release of large amounts of oxaliplatin. Studies using ovarian cancer xenotransplantation models have confirmed that these HER2-targeted, MMP-sensitive liposomes have higher anticancer activity than nontargeted, noncleavable liposomes.447 To address acquired resistance and side effects associated with EGFR-TKIs in NSCLC treatment, Zhang et al. synthesized biodegradable coordination polymers (dGNPs) incorporating EGFR-TKIs by using guanine deoxynucleotides and iron. In vivo, combining dGNP treatment with a fasting-mimicking diet yielded significant anticancer efficacy with reduced side effects.448 Therefore, RTK-targeting NDDSs have potential for further development.Chimeric antigen receptor cell therapyChimeric antigen receptor (CAR) technology is revolutionary, enabling the engineering of immune cells to target malignancies precisely. This modular receptor comprises four key components: an extracellular domain for antigen recognition, a hinge region, a transmembrane domain, and an intracellular signaling domain activating cytotoxic responses after target engagement.449 CAR-T cells were first demonstrated to have substantial efficacy in cancer immunotherapy. Thereafter, innate immune cells, such as CAR-engineered NK cells and macrophages, also demonstrated considerable therapeutic potential.450 Although CAR-T therapy has achieved major breakthroughs in the treatment of hematological malignancies, research progress on its applicability in the treatment of solid tumors has been more limited. RTK-targeting CAR-T strategies provide a promising frontier for solid tumor treatment; however, these approaches are still predominantly in preclinical and early-phase clinical stages.Clinical trials on RTK-targeting CAR-T cells for various cancers, including pancreatic cancer,451 recurrent GBM,452 chronic lymphocytic leukemia,453 and head and neck squamous carcinoma,449 as well as targets including EGFR, EGFRvIII, HER2, and ROR1, have reported high efficacy and safe outcomes. CAR-NK cells have also been reported to exert considerable cytotoxic effects against cancer cells. However, the efficacy of CAR-NK therapy alone may be limited due to tumor heterogeneity.454 Consequently, most recent studies have integrated CAR-NK cells with other treatments, including ICIs455 or oncolytic viruses.456 Using CAR-NK cell-derived biomimetic drug delivery systems is also a viable strategy. Tao et al. combined CAR-NK cell-derived exosomes and nanobombs and reported a potent effect against HER2-positive breast cancer brain metastasis in mice, resulting in notably extended survival.457In summary, RTK-targeted CAR-T and CAR-NK therapies have demonstrated promising results in preclinical studies and early-phase clinical trials for certain malignancies. However, their development remains in the early stages, and further investigation into the potential of additional RTK targets is essential. An ideal RTK target should possess at least one of these characteristics: (1) high expression in cancer cells but low expression in normal tissues, or (2) an extracellular domain harboring an oncogenic mutation that generates a novel cancer-specific antigen. Such cancer-specific antigens can allow CAR cells to precisely distinguish cancer cells from healthy cells, potentially creating a safety window for more targeted and safer therapeutic strategies.RNA interferenceRNA interference (RNAi) is a powerful tool for gene silencing that can target specific genes through exogenous small double-stranded RNA molecules, such as small interfering RNA (siRNA) and microRNA mimics.458 These molecules mediate gene silencing by forming an RNA-induced silencing complex with Argonaute-2, offering a potential therapeutic strategy for RTK dysregulation.459 At present, only a few studies have assessed RNAi for RTK-targeted therapy; however, one clinical trial each on EphA2 and VEGFR has reported promising clinical outcomes.460,461 For instance, Landen et al. developed neutral DOPC liposomes carrying EphA2-targeting siRNA (siRNA-EphA2-DOPC) and applied them to an ovarian cancer mouse model; the results demonstrated that the siRNA specifically targeting the antigen showed higher efficacy than nonspecific sequences.460 Another clinical trial evaluated the efficacy of intravitreal injection of VEGFR1-targeting siRNA in patients with choroidal neovascularization due to nAMD and noted stabilization or improvement in vision and foveal thickness.461 Thus, RNAi might have therapeutic potential in RTK-associated noncancerous conditions. However, RNAi therapy also has several limitations, including the saturation of endogenous RNAi machinery, unintended immune activation,462 and off-target gene silencing.463CRISPR/Cas9CRISPR/Cas9, a powerful genome-editing tool derived from bacterial immune systems, enables precise DNA modifications through RNA-guided Cas9 nuclease activity. In contrast to siRNA-mediated transient gene silencing, CRISPR/Cas9 can permanently disrupt or correct faulty genes.464 At present, CRISPR/Cas9 for RTK is focused mainly on lung cancer, with targets involving EGFR, IGF1R, ALK, and MET.465 Koo et al. used adenovirus (Ad) to deliver oncogenic mutation-specific CRISPR/Cas9 to precisely cleave and inactivate the mutated EGFR allele, significantly inhibiting growth and proliferation in lung cancer cell lines and reducing tumor growth in mouse lung cancer xenograft models.466 Thus, CRISPR/Cas9 may aid in targeting cancers with specific mutations or drug resistance and possess potential advantages in personalized cancer treatment compared with conventional therapies. However, the potential off-target effects and the lack of safe and efficient delivery systems have impeded the clinical application of CRISPR/Cas9.465TPDTargeted protein degradation (TPD), an emerging technology, involves eliminating pathogenic proteins through the activation of degradation pathways such as the ubiquitin–proteasome system (UPS) and lysosomal pathways.467 Common TPD technologies, including proteolysis targeting chimera (PROTAC), molecular glue (MG), and lysosome targeting chimera (LYTAC), have all been used for the degradation of abnormal RTKs in preclinical studies.PROTAC and MG can be used mainly to directly target intracellular and membrane-bound proteins to E3-ubiquitin ligases for degradation via the UPS.468 Because RTKs are the most remarkable anticancer targets and many RTK inhibitors can serve as building blocks, RTKs have become feasible PROTAC targets.469 Compared with RTK inhibitors, PROTACs exhibit potent and sustained signal inactivation and growth inhibition. Powell et al. developed small-molecule PROTACs targeting ALK for degradation, thereby suppressing its downstream signaling.470 HSK40118, an EGFR-targeting PROTAC, is in clinical trials.471 Wang et al. recently identified bardoxolone methyl (CDDO-Me) as an MG that directly binds to the kinase domain of EGFR, resulting in its ubiquitination and degradation. As such, CDDO-Me inhibits TNBC progression by promoting EGFR degradation.472 Thus, TPD may be a promising approach for RTK-targeted therapy.LYTAC, a new technology, can be used to induce protein degradation through the endosome–lysosome pathway. In contrast to PROTACs and MGs, LYTACs mainly target extracellular proteins and membrane proteins.473 LYTACs can degrade EGFR in breast cancer and hepatoma cells,473 indicating their potential applicability in RTK-targeted therapy.The clinical application of TPD, however, has some limitations. For instance, PROTACs are associated with drug feasibility challenges because of their relatively large molecular weight, complex physicochemical properties, and dependence on ligands during design.474 Moreover, MGs require phenotypic screening for identification and lack a reasonable design; thus, additional efforts are needed for their systematic clinical application.468Ligand-targeted therapyLigand-targeted therapy is a type of RTK-targeted therapy. Similar basic principles underlie therapeutic approaches targeting varied ligands: using a certain drug or biological agent (e.g., a small-molecule drug, therapeutic antibody or soluble receptor) to reduce ligand number or prevent ligand–RTK binding, thereby reducing RTK activation. Warfarin, a commonly used anticoagulant, can impair the function of GAS6 by preventing its γ-carboxylation475 and blocking GAS6-mediated activation of its receptor TAM and downstream signals, thus exerting antimetastatic effects. Preclinical studies have investigated the capacity of warfarin to disrupt GAS6 function in pancreatic, melanoma, and breast cancer models.476,477,478 Bevacizumab, a VEGFA-targeting mAb, was the first approved angiogenesis inhibitor and is applicable for several cancers, including metastatic breast cancer, NSCLC, and GBM.479Soluble receptors are currently the commonly used biological agents in RTK ligand-targeted therapy for RTK-related cancers and noncancerous conditions. The soluble AXL receptor MYD1, which has a strong affinity for GAS6, effectively inhibits GAS6-induced AXL phosphorylation and subsequent AKT and ERK activation, thereby reducing peritoneal metastases in ovarian cancer models.480 FP-1039, a soluble FGFR that can capture FGF, demonstrated anticancer effects in mouse models of lung cancer with FGFR1 amplification and endometrial cancer with mutations in FGFR2.481 Newer methods, such as liposome use and RNAi, have also been applied in RTK ligand-targeted therapy. For instance, Tabernero et al. designed the lipid NP formulation ALN-VSP to deliver VEGF and driver protein kinesin spindle protein (KSP) siRNA and observed its encouraging pharmacodynamics and anticancer activities in patients with multiple VEGF-overexpressing tumors.482 Notably, systemic toxicity due to VEGF and KSP inhibition was not observed, suggesting that this approach may yield a manageable safety profile.Conclusion and future perspectivesRTKs are pivotal hubs in cellular signaling networks, with well-established pathogenic roles in a spectrum of conditions. Although the cascade mechanisms of RTK signaling have been largely clarified, new ligands, activation modes, and downstream signaling modules continue to be identified. In research on RTK-targeted therapies, a key challenge lies in deciphering the context-dependent mechanisms of RTK signaling. It requires a quantitative analysis of RTK signaling within specific pathological environments to identify the key cell types involved in the disease, the ligand–receptor landscape, and the subcellular localization and compartmentalization of signaling events. Precise mapping of these dimensions is essential for developing specific therapies with minimal side effects.In cancer, RTK-targeted therapies, such as the multikinase inhibitors nintedanib and lenvatinib, have demonstrated considerable clinical efficacy, effectively extending patient survival; however, resistance and toxicity remain major challenges. To address these challenges, small-molecule inhibitors are evolving in three key areas: enhanced selectivity (from broad-spectrum to subtype-specific), increased potency (through structure-guided design), and improved resistance management (via allosteric or covalent inhibition).34 In addition to classical strategies, emerging modalities such as PROTACs and bispecific antibody-based agents offer new avenues for overcoming resistance mechanisms and bypassing activation. Finally, rational drug combinations, such as combining RTK inhibitors with immune checkpoint blockade or chemotherapy, represent a promising strategy to achieve more durable disease control.In noncancerous conditions, the rationale for targeting RTKs is strong; however, clinical translation of relevant therapies remains challenging, with far fewer of them approved than those for cancer treatment. In contrast to cancer, many noncancerous conditions are chronic and not immediately life-threatening, making the maintenance of a favorable therapeutic risk–benefit balance and quality of life crucial considerations for the affected patients. In some cases, the side effects of systemic RTK inhibition may outweigh the benefits, necessitating advanced strategies such as localized delivery, low-dose regimens, or cell-specific targeting to maximize efficacy without worsening toxicity.In conclusion, the position of RTK signaling as a biological hub indicates its potential as a core target for treating diseases. Recently, single-cell omics has significantly advanced the definition of spatiotemporal characteristics of diseases with abnormal RTK signaling.483,484,485,486 Moreover, advanced structural biology techniques, such as cryoelectron microscopy, in conjunction with artificial intelligence-driven protein structure prediction platforms, are being employed to generate transformative opportunities for the elucidation of RTK signaling mechanisms and expedited structure-guided drug discovery.487,488,489 Notably, current research on RTKs is highly focused on the few key receptors driving cancer progression, such as EGFR, FGFR, MET, PDGFR, and VEGFR. The functions and therapeutic values of more than half of all RTK family members require further elucidation. Moreover, to overcome the limitations of traditional cell models, adopting a quantitative analysis framework and validating findings in more physiologically relevant human disease models, such as multiorgan-on-chip systems, is crucial for bridging basic discoveries and clinical translation.490 Collectively, these efforts will drive the development of more precise RTK-targeted therapeutic strategies, eventually enhancing therapeutic outcomes and quality of life in affected patients.ReferencesUshiro, H. & Cohen, S. Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J. Biol. Chem. 255, 8363–8365 (1980).Article PubMed CAS Google Scholar Kasuga, M., Zick, Y., Blithe, D. L., Crettaz, M. & Kahn, C. R. Insulin stimulates tyrosine phosphorylation of the insulin receptor in a cell-free system. Nature 298, 667–669 (1982).Article PubMed CAS Google Scholar Ek, B., Westermark, B., Wasteson, A. & Heldin, C. H. Stimulation of tyrosine-specific phosphorylation by platelet-derived growth factor. Nature 295, 419–420 (1982).Article PubMed CAS Google Scholar Jeon, M. & Zinn, K. Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of Egfr signaling. Development 136, 3121–3129 (2009).Article PubMed PubMed Central CAS Google Scholar Covassin, L. D., Villefranc, J. A., Kacergis, M. C., Weinstein, B. M. & Lawson, N. D. Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish. Proc. Natl. Acad. Sci. USA 103, 6554–6559 (2006).Article PubMed PubMed Central CAS Google Scholar Aroian, R. V., Koga, M., Mendel, J. E., Ohshima, Y. & Sternberg, P. W. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature 348, 693–699 (1990).Article PubMed CAS Google Scholar Chamorro, M. N. et al. FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development. EMBO J 24, 73–84 (2005).Article PubMed CAS Google Scholar Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).Article PubMed PubMed Central CAS Google Scholar Du, Z. & Lovly, C. M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer 17, 58 (2018).Article PubMed PubMed Central Google Scholar de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).Article PubMed Google Scholar DeRyckere, D., Huelse, J. M., Earp, H. S. & Graham, D. K. TAM family kinases as therapeutic targets at the interface of cancer and immunity. Nat. Rev. Clin. Oncol. 20, 755–779 (2023).Article PubMed Google Scholar Tomuleasa, C. et al. Therapeutic advances of targeting receptor tyrosine kinases in cancer. Signal Transduct. Target Ther. 9, 201 (2024).Article PubMed PubMed Central CAS Google Scholar Ebrahimi, N. et al. Receptor tyrosine kinase inhibitors in cancer. Cell. Mol. Life Sci. 80, 104 (2023).Article PubMed PubMed Central CAS Google Scholar Gai, X. et al. GOLM1 PromOtes Atherogenesis By Activating Macrophage EGFR-ERK signaling cascade. Circ. Res. 136, 848–861 (2025).Article PubMed CAS Google Scholar Antonijevic, M., Dallemagne, P. & Rochais, C. Indirect influence on the BDNF/TrkB receptor signaling pathway via GPCRs, an emerging strategy in the treatment of neurodegenerative disorders. Med. Res. Rev. 45, 274–310 (2025).Article PubMed CAS Google Scholar Chen, X. et al. Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes. Acta Pharm. Sin. B 14, 1693–1710 (2024).Article PubMed PubMed Central CAS Google Scholar Cohen, S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J. Biol. Chem. 237, 1555–1562 (1962).Article PubMed CAS Google Scholar Carpenter, G. & Cohen, S. 125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts. J. Cell Biol. 71, 159–171 (1976).Article PubMed PubMed Central CAS Google Scholar Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).Article PubMed CAS Google Scholar Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. Nature 312, 513–516 (1984).Article PubMed CAS Google Scholar Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).Article PubMed CAS Google Scholar Franco, C. et al. Discoidin domain receptor 1 on bone marrow-derived cells promotes macrophage accumulation during atherogenesis. Circ. Res. 105, 1141–1148 (2009).Article PubMed CAS Google Scholar Zhou, J. et al. Tyro3, Axl, and Mertk receptors differentially participate in platelet activation and thrombus formation. Cell Commun. Signal. 16, 98 (2018).Article PubMed PubMed Central CAS Google Scholar Song, Y. et al. Tyrosine kinase receptor B attenuates liver fibrosis by inhibiting TGF-β/SMAD signaling. Hepatology 78, 1433–1447 (2023).Article PubMed PubMed Central Google Scholar Sasaki, T. et al. Structural basis for Gas6-Axl signalling. EMBO J 25, 80–87 (2006).Article PubMed CAS Google Scholar Wiesmann, C. et al. Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91, 695–704 (1997).Article PubMed CAS Google Scholar Barton, W. A. et al. Crystal structures of the Tie2 receptor ectodomain and the angiopoietin-2-Tie2 complex. Nat. Struct. Mol. Biol. 13, 524–532 (2006).Article PubMed CAS Google Scholar Wu, Q., Qian, W., Sun, X. & Jiang, S. Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021. J. Hematol. Oncol. 15, 143 (2022).Article PubMed PubMed Central CAS Google Scholar Burstein, H. J. et al. Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer. J. Clin. Oncol. 19, 2722–2730 (2001).Article PubMed CAS Google Scholar Cohen, M. H., Williams, G. A., Sridhara, R., Chen, G. & Pazdur, R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist 8, 303–306 (2003).Article PubMed CAS Google Scholar Noronha, V. et al. Gefitinib versus gefitinib plus pemetrexed and carboplatin chemotherapy in EGFR-mutated lung cancer. J. Clin. Oncol. 38, 124–136 (2020).Article PubMed CAS Google Scholar Ng, E. W. et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat. Rev. Drug Discov. 5, 123–132 (2006).Article PubMed CAS Google Scholar Gragoudas, E. S., Adamis, A. P., Cunningham, E. T. Jr., Feinsod, M. & Guyer, D. R. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 351, 2805–2816 (2004).Article PubMed CAS Google Scholar Yang, Y., Li, S., Wang, Y., Zhao, Y. & Li, Q. Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective. Signal Transduct. Target Ther. 7, 329 (2022).Article PubMed PubMed Central CAS Google Scholar Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790. Mater. Nat. Med. 21, 560–562 (2015).Article CAS Google Scholar Ma, B. et al. Kill two birds with one stone: a multifunctional dual-targeting protein drug to overcome imatinib resistance in Philadelphia chromosome-positive leukemia. Adv. Sci. 9, e2104850 (2022).Article Google Scholar Tan, C. S. et al. Third-generation EGFR TKIs: current data and future directions. Mol. Cancer 17, 29 (2018).Article PubMed PubMed Central Google Scholar George, B. et al. Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALK(+) T-cell lymphoma. J. Hematol. Oncol. 12, 80 (2019).Article PubMed PubMed Central Google Scholar Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).Article PubMed CAS Google Scholar Boudeau, J., Miranda-Saavedra, D., Barton, G. J. & Alessi, D. R. Emerging roles of pseudokinases. Trends Cell Biol. 16, 443–452 (2006).Article PubMed CAS Google Scholar Katso, R. M., Russell, R. B. & Ganesan, T. S. Functional analysis of H-Ryk, an atypical member of the receptor tyrosine kinase family. Mol. Cell. Biol. 19, 6427–6440 (1999).Article PubMed PubMed Central CAS Google Scholar Gentile, A., Lazzari, L., Benvenuti, S., Trusolino, L. & Comoglio, P. M. Ror1 is a pseudokinase that is crucial for Met-driven tumorigenesis. Cancer Res. 71, 3132–3141 (2011).Article PubMed CAS Google Scholar Debebe, Z. & Rathmell, W. K. Ror2 as a therapeutic target in cancer. Pharmacol. Ther. 150, 143–148 (2015).Article PubMed PubMed Central CAS Google Scholar Kung, J. E. & Jura, N. Prospects for pharmacological targeting of pseudokinases. Nat. Rev. Drug Discov. 18, 501–526 (2019).Article PubMed PubMed Central CAS Google Scholar Suga, H., Torruella, G., Burger, G., Brown, M. W. & Ruiz-Trillo, I. Earliest holozoan expansion of phosphotyrosine signaling. Mol. Biol. Evol. 31, 517–528 (2014).Article PubMed CAS Google Scholar Shrivastava, A. et al. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1, 25–34 (1997).Article PubMed CAS Google Scholar Rasool, D. & Jahani-Asl, A. Master regulators of neurogenesis: the dynamic roles of Ephrin receptors across diverse cellular niches. Transl. Psychiatry 14, 462 (2024).Article PubMed PubMed Central Google Scholar Pasquale, E. B. Eph receptors and ephrins in cancer progression. Nat. Rev. Cancer 24, 5–27 (2024).Article PubMed CAS Google Scholar Ward, C. et al. Structural insights into ligand-induced activation of the insulin receptor. Acta Physiol. 192, 3–9 (2008).Article CAS Google Scholar Himanen, J. P. & Nikolov, D. B. Eph signaling: a structural view. Trends Neurosci. 26, 46–51 (2003).Article PubMed CAS Google Scholar Chung, I. et al. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 464, 783–787 (2010).Article PubMed CAS Google Scholar Soos, M. A., Field, C. E. & Siddle, K. Purified hybrid insulin/insulin-like growth factor-I receptors bind insulin-like growth factor-I, but not insulin, with high affinity. Biochem. J. 290, 419–426 (1993).Article PubMed PubMed Central CAS Google Scholar Huse, M. & Kuriyan, J. The conformational plasticity of protein kinases. Cell 109, 275–282 (2002).Article PubMed CAS Google Scholar Stamos, J., Sliwkowski, M. X. & Eigenbrot, C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J. Biol. Chem. 277, 46265–46272 (2002).Article PubMed CAS Google Scholar Mol, C. D. et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J. Biol. Chem. 278, 31461–31464 (2003).Article PubMed CAS Google Scholar Favelyukis, S., Till, J. H., Hubbard, S. R. & Miller, W. T. Structure and autoregulation of the insulin-like growth factor 1 receptor kinase. Nat. Struct. Biol. 8, 1058–1063 (2001).Article PubMed CAS Google Scholar Hubbard, S. R. Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog. EMBO J. 16, 5572–5581 (1997).Article PubMed PubMed Central CAS Google Scholar McTigue, M. A. et al. Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis. Structure 7, 319–330 (1999).Article PubMed CAS Google Scholar Nolen, B., Taylor, S. & Ghosh, G. Regulation of protein kinases; controlling activity through activation segment conformation. Mol. Cell 15, 661–675 (2004).Article PubMed CAS Google Scholar Bae, J. H. et al. The selectivity of receptor tyrosine kinase signaling is controlled by a secondary SH2 domain binding site. Cell 138, 514–524 (2009).Article PubMed PubMed Central CAS Google Scholar Chen, H. et al. A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Mol. Cell 27, 717–730 (2007).Article PubMed PubMed Central Google Scholar Hubbard, S. R. Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat. Rev. Mol. Cell Biol. 5, 464–470 (2004).Article PubMed CAS Google Scholar Wybenga-Groot, L. E. et al. Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106, 745–757 (2001).Article PubMed CAS Google Scholar Kimura, Y. et al. Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages. Proc. Natl. Acad. Sci. USA 101, 6015–6020 (2004).Article PubMed PubMed Central CAS Google Scholar Heiss, E. et al. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood 108, 1542–1550 (2006).Article PubMed CAS Google Scholar Liang, L., Yan, X. E., Yin, Y. & Yun, C. H. Structural and biochemical studies of the PDGFRA kinase domain. Biochem. Biophys. Res. Commun. 477, 667–672 (2016).Article PubMed CAS Google Scholar Niu, X. L., Peters, K. G. & Kontos, C. D. Deletion of the carboxyl terminus of Tie2 enhances kinase activity, signaling, and function: evidence for an autoinhibitory mechanism. J. Biol. Chem. 277, 31768–31773 (2002).Article PubMed CAS Google Scholar Shewchuk, L. M. et al. Structure of the Tie2 RTK domain: self-inhibition by the nucleotide binding loop, activation loop, and C-terminal tail. Structure 8, 1105–1113 (2000).Article PubMed CAS Google Scholar Yokoyama, N., Ischenko, I., Hayman, M. J. & Miller, W. T. The C terminus of RON tyrosine kinase plays an autoinhibitory role. J. Biol. Chem. 280, 8893–8900 (2005).Article PubMed CAS Google Scholar Chiara, F., Bishayee, S., Heldin, C. H. & Demoulin, J. B. Autoinhibition of the platelet-derived growth factor beta-receptor tyrosine kinase by its C-terminal tail. J. Biol. Chem. 279, 19732–19738 (2004).Article PubMed CAS Google Scholar Zhang, X., Gureasko, J., Shen, K., Cole, P. A. & Kuriyan, J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell 125, 1137–1149 (2006).Article PubMed CAS Google Scholar Wieduwilt, M. J. & Moasser, M. M. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell. Mol. Life Sci. 65, 1566–1584 (2008).Article PubMed PubMed Central CAS Google Scholar Carraway, K. L. 3rd & Sweeney, C. EGF receptor activation by heterologous mechanisms. Cancer Cell 1, 405–406 (2002).Article PubMed CAS Google Scholar Zhang, Y. et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol. Cancer 17, 45 (2018).Article PubMed PubMed Central Google Scholar Yao, H. P., Zhou, Y. Q., Zhang, R. & Wang, M. H. MSP-RON signalling in cancer: pathogenesis and therapeutic potential. Nat. Rev. Cancer 13, 466–481 (2013).Article PubMed CAS Google Scholar Osta, B. E. & Ramalingam, S. S. RET fusion: joining the ranks of targetable molecular drivers in NSCLC. JTO Clin. Res. Rep. 1, 100050 (2020).PubMed PubMed Central Google Scholar Lu, Y., Yao, H. P. & Wang, M. H. Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets. Cancer Lett. 257, 157–164 (2007).Article PubMed CAS Google Scholar Domenichini, M. et al. The D647N mutation of FGFR1 induces ligand-independent receptor activation. Biochim. Biophys. Acta Gen. Subj. 1867, 130470 (2023).Article PubMed CAS Google Scholar Ruan, Z. & Kannan, N. Altered conformational landscape and dimerization dependency underpins the activation of EGFR by αC-β4 loop insertion mutations. Proc. Natl. Acad. Sci. USA 115, E8162–E8171 (2018).Article PubMed PubMed Central CAS Google Scholar Dhalluin, C. et al. Structural basis of SNT PTB domain interactions with distinct neurotrophic receptors. Mol. Cell 6, 921–929 (2000).Article PubMed PubMed Central CAS Google Scholar LaRochelle, J. R. et al. Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition. Nat. Commun. 9, 4508 (2018).Article PubMed PubMed Central Google Scholar Wang, M. et al. Blockade of phosphotyrosine pathways suggesting SH2 superbinder as a novel therapy for pulmonary fibrosis. Theranostics 12, 4513–4535 (2022).Article PubMed PubMed Central CAS Google Scholar Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85–96 (2006).Article PubMed CAS Google Scholar Tari, A. M., Hung, M. C., Li, K. & Lopez-Berestein, G. Growth inhibition of breast cancer cells by Grb2 downregulation is correlated with inactivation of mitogen-activated protein kinase in EGFR, but not in ErbB2, cells. Oncogene 18, 1325–1332 (1999).Article PubMed CAS Google Scholar Yang, Z. et al. The signaling adaptor GAB1 regulates cell polarity by acting as a PAR protein scaffold. Mol. Cell 47, 469–483 (2012).Article PubMed PubMed Central CAS Google Scholar Nagao, H. et al. Leucine-973 is a crucial residue differentiating insulin and IGF-1 receptor signaling. J. Clin. Investig. 133, e161472 (2023).Article PubMed PubMed Central CAS Google Scholar Peterson, A. F. et al. Systematic analysis of the MAPK signaling network reveals MAP3K-driven control of cell fate. Cell Syst. 13, 885–894.e884 (2022).Article PubMed PubMed Central CAS Google Scholar Oda, K., Matsuoka, Y., Funahashi, A. & Kitano, H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 1, 2005.0010 (2005).Article PubMed PubMed Central Google Scholar Kouhara, H. et al. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell 89, 693–702 (1997).Article PubMed CAS Google Scholar Choi, E., Duan, C. & Bai, X. C. Regulation and function of insulin and insulin-like growth factor receptor signalling. Nat. Rev. Mol. Cell Biol. 26, 558–580 (2025).Article PubMed PubMed Central CAS Google Scholar Volinsky, N. & Kholodenko, B. N. Complexity of receptor tyrosine kinase signal processing. Cold Spring Harb. Perspect. Biol. 5, a009043 (2013).Article PubMed PubMed Central Google Scholar Hua, H. et al. Targeting Akt in cancer for precision therapy. J. Hematol. Oncol. 14, 128 (2021).Article PubMed PubMed Central CAS Google Scholar Thorpe, L. M., Yuzugullu, H. & Zhao, J. J. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15, 7–24 (2015).Article PubMed PubMed Central CAS Google Scholar Miao, H. et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat. Cell Biol. 3, 527–530 (2001).Article PubMed CAS Google Scholar Miao, H. et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16, 9–20 (2009).Article PubMed PubMed Central CAS Google Scholar Macrae, M. et al. A conditional feedback loop regulates Ras activity through EphA2. Cancer Cell 8, 111–118 (2005).Article PubMed CAS Google Scholar Yang, N. Y. et al. Crosstalk of the EphA2 receptor with a serine/threonine phosphatase suppresses the Akt-mTORC1 pathway in cancer cells. Cell. Signal. 23, 201–212 (2011).Article PubMed CAS Google Scholar Obermeier, A. et al. Neuronal differentiation signals are controlled by nerve growth factor receptor/Trk binding sites for SHC and PLCγ. EMBO J. 13, 1585–1590 (1994).Article PubMed PubMed Central CAS Google Scholar Mandal, S., Bandyopadhyay, S., Tyagi, K. & Roy, A. Recent advances in understanding the molecular role of phosphoinositide-specific phospholipase C gamma 1 as an emerging onco-driver and novel therapeutic target in human carcinogenesis. Biochim. Biophys. Acta Rev. Cancer 1876, 188619 (2021).Article PubMed CAS Google Scholar Chen, D. & Simons, M. Emerging roles of PLCγ1 in endothelial biology. Sci. Signal. 14, eabc6612 (2021).Article PubMed PubMed Central CAS Google Scholar Medina, D. L. et al. TrkB regulates neocortex formation through the Shc/PLCgamma-mediated control of neuronal migration. EMBO J. 23, 3803–3814 (2004).Article PubMed PubMed Central CAS Google Scholar O’Shea, J. J., Holland, S. M. & Staudt, L. M. JAKs and STATs in immunity, immunodeficiency, and cancer. N. Engl. J. Med. 368, 161–170 (2013).Article PubMed PubMed Central Google Scholar Gherardi, E., Birchmeier, W., Birchmeier, C. & Vande Woude, G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 12, 89–103 (2012).Article PubMed CAS Google Scholar Shao, H., Cheng, H. Y., Cook, R. G. & Tweardy, D. J. Identification and characterization of signal transducer and activator of transcription 3 recruitment sites within the epidermal growth factor receptor. Cancer Res 63, 3923–3930 (2003).PubMed CAS Google Scholar Mali, S. B. Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol. 51, 565–569 (2015).Article PubMed CAS Google Scholar Taniguchi, K. & Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309–324 (2018).Article PubMed CAS Google Scholar Tey, S. K. et al. Nuclear Met promotes hepatocellular carcinoma tumorigenesis and metastasis by upregulation of TAK1 and activation of NF-κB pathway. Cancer Lett. 411, 150–161 (2017).Article PubMed CAS Google Scholar Ozes, O. N. et al. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401, 82–85 (1999).Article PubMed CAS Google Scholar Romashkova, J. A. & Makarov, S. S. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401, 86–90 (1999).Article PubMed CAS Google Scholar Salminen, A. & Kaarniranta, K. Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell. Signal. 22, 573–577 (2010).Article PubMed CAS Google Scholar Dan, H. C. et al. Akt-dependent regulation of NF-{kappa}B is controlled by mTOR and Raptor in association with IKK. Genes Dev 22, 1490–1500 (2008).Article PubMed PubMed Central CAS Google Scholar Nikolaidis, N. M. et al. Ron receptor tyrosine kinase negatively regulates tnfα production in alveolar macrophages by inhibiting nf-κb activity and adam17 production. Shock 33, 197–204 (2010).Article PubMed PubMed Central CAS Google Scholar Lee, Y. J. et al. Inhibiting Mer receptor tyrosine kinase suppresses STAT1, SOCS1/3, and NF-κB activation and enhances inflammatory responses in lipopolysaccharide-induced acute lung injury. J. Leukoc. Biol. 91, 921–932 (2012).Article PubMed CAS Google Scholar Yuk, J. M. et al. The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by Toll-like receptors. Nat. Immunol. 12, 742–751 (2011).Article PubMed CAS Google Scholar Pawson, T. Protein modules and signalling networks. Nature 373, 573–580 (1995).Article PubMed CAS Google Scholar Salokas, K. et al. Physical and functional interactome atlas of human receptor tyrosine kinases. EMBO Rep. 23, e54041 (2022).Article PubMed PubMed Central CAS Google Scholar Hakuno, F. & Takahashi, S. I. 40 years of IGF1: IGF1 receptor signaling pathways. J. Mol. Endocrinol. 61, T69–T86 (2018).Article PubMed CAS Google Scholar Myers, M. G. Jr & White, M. F. Insulin signal transduction and the IRS proteins. Annu. Rev. Pharmacol. Toxicol. 36, 615–658 (1996).Article PubMed CAS Google Scholar Bradshaw, R. A. et al. NGF and ProNGF: Regulation of neuronal and neoplastic responses through receptor signaling. Adv. Biol. Regul. 58, 16–27 (2015).Article PubMed CAS Google Scholar Gotoh, N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci. 99, 1319–1325 (2008).Article PubMed PubMed Central CAS Google Scholar Songyang, Z. & Cantley, L. C. ZIP codes for delivering SH2 domains. Cell 116, S41–S43 (2004). 2 p following S48.Article PubMed CAS Google Scholar Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).Article PubMed CAS Google Scholar Santos, S. D., Verveer, P. J. & Bastiaens, P. I. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nat. Cell Biol. 9, 324–330 (2007).Article PubMed CAS Google Scholar Kholodenko, B. N. Cell-signalling dynamics in time and space. Nat. Rev. Mol. Cell Biol. 7, 165–176 (2006).Article PubMed PubMed Central CAS Google Scholar Yeh, I. et al. Activating MET kinase rearrangements in melanoma and Spitz tumours. Nat. Commun. 6, 7174 (2015).Article PubMed PubMed Central Google Scholar Peschard, P. et al. Mutation of the c-Cbl TKB domain binding site on the Met receptor tyrosine kinase converts it into a transforming protein. Mol. Cell 8, 995–1004 (2001).Article PubMed CAS Google Scholar Lingwood, D. & Simons, K. Lipid rafts as a membrane-organizing principle. Science 327, 46–50 (2010).Article PubMed CAS Google Scholar Katoh, S. Y., Kamimoto, T., Yamakawa, D. & Takakura, N. Lipid rafts serve as signaling platforms for Tie2 receptor tyrosine kinase in vascular endothelial cells. Exp. Cell Res. 315, 2818–2823 (2009).Article PubMed CAS Google Scholar Palacios-Moreno, J. et al. Neuroblastoma tyrosine kinase signaling networks involve FYN and LYN in endosomes and lipid rafts. PLoS Comput. Biol. 11, e1004130 (2015).Article PubMed PubMed Central Google Scholar Zhang, G. et al. CD317 activates EGFR by regulating its association with lipid rafts. Cancer Res. 79, 2220–2231 (2019).Article PubMed PubMed Central CAS Google Scholar Pan, Z. et al. Cholesterol promotes EGFR-TKIs resistance in NSCLC by inducing EGFR/Src/Erk/SP1 signaling-mediated ERRα re-expression. Mol. Cancer 21, 77 (2022).Article PubMed PubMed Central CAS Google Scholar Gonzalez-Gaitan, M. The garden of forking paths: recycling, signaling, and degradation. Dev. Cell 15, 172–174 (2008).Article PubMed CAS Google Scholar Kermorgant, S. & Parker, P. J. Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation. J. Cell Biol. 182, 855–863 (2008).Article PubMed PubMed Central CAS Google Scholar Chen, Y. L. et al. Nuclear translocation of RON receptor tyrosine kinase. New mechanistic and functional insights. Cytokine Growth Factor Rev. 81, 9–15 (2025).Article PubMed CAS Google Scholar Kermorgant, S., Zicha, D. & Parker, P. J. PKC controls HGF-dependent c-Met traffic, signalling and cell migration. EMBO J. 23, 3721–3734 (2004).Article PubMed PubMed Central CAS Google Scholar Sigismund, S. et al. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev. Cell 15, 209–219 (2008).Article PubMed CAS Google Scholar Wu, K. et al. MSP-RON signaling in liver pathobiology and as an emerging therapeutic target: a review of the current evidence. Cell Commun. Signal. 23, 385 (2025).Article PubMed PubMed Central Google Scholar Sahni, M. et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev. 13, 1361–1366 (1999).Article PubMed PubMed Central CAS Google Scholar Kim, A. R. et al. Functional selectivity in cytokine signaling revealed through a pathogenic EPO mutation. Cell 168, 1053–1064.e1015 (2017).Article PubMed PubMed Central CAS Google Scholar Lazzara, M. J. & Lauffenburger, D. A. Quantitative modeling perspectives on the ErbB system of cell regulatory processes. Exp. Cell Res. 315, 717–725 (2009).Article PubMed CAS Google Scholar Wiley, H. S., Shvartsman, S. Y. & Lauffenburger, D. A. Computational modeling of the EGF-receptor system: a paradigm for systems biology. Trends Cell Biol. 13, 43–50 (2003).Article PubMed CAS Google Scholar Kumar, N., Afeyan, R., Kim, H. D. & Lauffenburger, D. A. Multipathway model enables prediction of kinase inhibitor cross-talk effects on migration of Her2-overexpressing mammary epithelial cells. Mol. Pharmacol. 73, 1668–1678 (2008).Article PubMed PubMed Central CAS Google Scholar LeCun, Y., Bengio, Y. & Hinton, G. Deep learning. Nature 521, 436–444 (2015).Article PubMed CAS Google Scholar Hartman, E. et al. Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis. Nat. Commun. 14, 5359 (2023).Article PubMed PubMed Central CAS Google Scholar Nardini, J. T. Forecasting and predicting stochastic agent-based model data with biologically-informed neural networks. Bull. Math. Biol. 86, 130 (2024).Article PubMed Google Scholar Abu-Remaileh, M. et al. Visions of the future of molecular cell biology. Nat. Rev. Mol. Cell Biol. 26, 735–740 (2025).Article PubMed CAS Google Scholar Bunne, C. et al. How to build the virtual cell with artificial intelligence: priorities and opportunities. Cell 187, 7045–7063 (2024).Article PubMed PubMed Central CAS Google Scholar Latorraca, N. R., Venkatakrishnan, A. J. & Dror, R. O. GPCR dynamics: structures in motion. Chem. Rev. 117, 139–155 (2017).Article PubMed CAS Google Scholar Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schiöth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).Article PubMed PubMed Central CAS Google Scholar Dunn, H. A., Orlandi, C. & Martemyanov, K. A. Beyond the ligand: extracellular and transcellular G protein-coupled receptor complexes in physiology and pharmacology. Pharmacol. Rev. 71, 503–519 (2019).Article PubMed PubMed Central CAS Google Scholar Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).Article PubMed CAS Google Scholar Eguchi, S., Dempsey, P. J., Frank, G. D., Motley, E. D. & Inagami, T. Activation of MAPKs by angiotensin II in vascular smooth muscle cells. Metalloprotease-dependent EGF receptor activation is required for activation of ERK and p38 MAPK but not for JNK. J. Biol. Chem. 276, 7957–7962 (2001).Article PubMed CAS Google Scholar Kalmes, A., Vesti, B. R., Daum, G., Abraham, J. A. & Clowes, A. W. Heparin blockade of thrombin-induced smooth muscle cell migration involves inhibition of epidermal growth factor (EGF) receptor transactivation by heparin-binding EGF-like growth factor. Circ. Res. 87, 92–98 (2000).Article PubMed CAS Google Scholar Hao, L., Du, M., Lopez-Campistrous, A. & Fernandez-Patron, C. Agonist-induced activation of matrix metalloproteinase-7 promotes vasoconstriction through the epidermal growth factor-receptor pathway. Circ. Res. 94, 68–76 (2004).Article PubMed CAS Google Scholar Carbajal, L., Biswas, A., Niswander, L. M., Prizant, H. & Hammes, S. R. GPCR/EGFR cross-talk is conserved in gonadal and adrenal steroidogenesis but is uniquely regulated by matrix metalloproteinases 2 and 9 in the ovary. Mol. Endocrinol. 25, 1055–1065 (2011).Article PubMed PubMed Central CAS Google Scholar Biscardi, J. S. et al. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J. Biol. Chem. 274, 8335–8343 (1999).Article PubMed CAS Google Scholar Keely, S. J., Calandrella, S. O. & Barrett, K. E. Carbachol-stimulated transactivation of epidermal growth factor receptor and mitogen-activated protein kinase in T(84) cells is mediated by intracellular Ca2+, PYK-2, and p60(src). J. Biol. Chem. 275, 12619–12625 (2000).Article PubMed CAS Google Scholar Tsai, C. L. et al. c-Src-dependent transactivation of PDGFR contributes to TNF-α-induced MMP-9 expression and functional impairment in osteoblasts. Bone 60, 186–197 (2014).Article PubMed CAS Google Scholar Fischer, O. M., Giordano, S., Comoglio, P. M. & Ullrich, A. Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J. Biol. Chem. 279, 28970–28978 (2004).Article PubMed CAS Google Scholar Cattaneo, F., Iaccio, A., Guerra, G., Montagnani, S. & Ammendola, R. NADPH-oxidase-dependent reactive oxygen species mediate EGFR transactivation by FPRL1 in WKYMVm-stimulated human lung cancer cells. Free Radic. Biol. Med. 51, 1126–1136 (2011).Article PubMed CAS Google Scholar El Zein, N., D’Hondt, S. & Sariban, E. Crosstalks between the receptors tyrosine kinase EGFR and TrkA and the GPCR, FPR, in human monocytes are essential for receptors-mediated cell activation. Cell. Signal. 22, 1437–1447 (2010).Article PubMed CAS Google Scholar Crudden, C. et al. Blurring boundaries: receptor tyrosine kinases as functional G protein-coupled receptors. Int. Rev. Cell Mol. Biol. 339, 1–40 (2018).PubMed CAS Google Scholar Hallak, H., Seiler, A. E., Green, J. S., Ross, B. N. & Rubin, R. Association of heterotrimeric G(i) with the insulin-like growth factor-I receptor. Release of G(betagamma) subunits upon receptor activation. J. Biol. Chem. 275, 2255–2258 (2000).Article PubMed CAS Google Scholar Heyworth, C. M., Grey, A. M., Wilson, S. R., Hanski, E. & Houslay, M. D. The action of islet activating protein (pertussis toxin) on insulin’s ability to inhibit adenylate cyclase and activate cyclic AMP phosphodiesterases in hepatocytes. Biochem. J. 235, 145–149 (1986).Article PubMed PubMed Central CAS Google Scholar Tilley, D. G., Kim, I. M., Patel, P. A., Violin, J. D. & Rockman, H. A. beta-Arrestin mediates beta1-adrenergic receptor-epidermal growth factor receptor interaction and downstream signaling. J. Biol. Chem. 284, 20375–20386 (2009).Article PubMed PubMed Central CAS Google Scholar Alderton, F. et al. Tethering of the platelet-derived growth factor beta receptor to G-protein-coupled receptors. A novel platform for integrative signaling by these receptor classes in mammalian cells. J. Biol. Chem. 276, 28578–28585 (2001).Article PubMed CAS Google Scholar Rakhit, S., Pyne, S. & Pyne, N. J. Nerve growth factor stimulation of p42/p44 mitogen-activated protein kinase in PC12 cells: role of G(i/o), G protein-coupled receptor kinase 2, beta-arrestin I, and endocytic processing. Mol. Pharmacol. 60, 63–70 (2001).Article PubMed CAS Google Scholar Dalle, S. et al. Insulin induces heterologous desensitization of G-protein-coupled receptor and insulin-like growth factor I signaling by downregulating beta-arrestin-1. Mol. Cell. Biol. 22, 6272–6285 (2002).Article PubMed PubMed Central CAS Google Scholar Girnita, L., Janssen, J. & Smith, T. J. G-protein coupled & membrane tyrosine kinase receptors relationship yield therapy opportunities. Endocr. Rev. 46, 810–837 (2025).Article PubMed CAS Google Scholar Di Liberto, V., Mudò, G. & Belluardo, N. Crosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) in the brain: Focus on heteroreceptor complexes and related functional neurotrophic effects. Neuropharmacology 152, 67–77 (2019).Article PubMed Google Scholar Hayat, R., Manzoor, M. & Hussain, A. Wnt signaling pathway: a comprehensive review. Cell Biol. Int. 46, 863–877 (2022).Article PubMed CAS Google Scholar Zeng, X. et al. A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 438, 873–877 (2005).Article PubMed PubMed Central CAS Google Scholar Georgopoulos, N. T., Kirkwood, L. A. & Southgate, J. A novel bidirectional positive-feedback loop between Wnt-β-catenin and EGFR-ERK plays a role in context-specific modulation of epithelial tissue regeneration. J. Cell Sci. 127, 2967–2982 (2014).PubMed PubMed Central CAS Google Scholar Prossomariti, A., Piazzi, G., Alquati, C. & Ricciardiello, L. Are Wnt/β-catenin and PI3K/AKT/mTORC1 distinct pathways in colorectal cancer? Cell. Mol. Gastroenterol. Hepatol. 10, 491–506 (2020).Article PubMed PubMed Central Google Scholar Voutsadakis, I. A. The ubiquitin-proteasome system and signal transduction pathways regulating Epithelial-Mesenchymal transition of cancer. J. Biomed. Sci. 19, 67 (2012).Article PubMed PubMed Central CAS Google Scholar Hu, T. & Li, C. Convergence between Wnt-β-catenin and EGFR signaling in cancer. Mol. Cancer 9, 236 (2010).Article PubMed PubMed Central Google Scholar Green, J., Nusse, R. & van Amerongen, R. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb. Perspect. Biol. 6, a009175 (2014).Article PubMed PubMed Central Google Scholar De, A. Wnt/Ca2+ signaling pathway: a brief overview. Acta Biochim. Biophys. Sin. 43, 745–756 (2011).Article PubMed CAS Google Scholar Kikuchi, A., Yamamoto, H. & Kishida, S. Multiplicity of the interactions of Wnt proteins and their receptors. Cell. Signal. 19, 659–671 (2007).Article PubMed CAS Google Scholar Nishita, M. et al. Filopodia formation mediated by receptor tyrosine kinase Ror2 is required for Wnt5a-induced cell migration. J. Cell Biol. 175, 555–562 (2006).Article PubMed PubMed Central CAS Google Scholar Guo, X. & Wang, X. F. A mediator lost in the war on cancer. Cell 151, 927–929 (2012).Article PubMed CAS Google Scholar Li, M. O. & Flavell, R. A. TGF-beta: a master of all T cell trades. Cell 134, 392–404 (2008).Article PubMed PubMed Central CAS Google Scholar Jechlinger, M. et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Investig. 116, 1561–1570 (2006).Article PubMed PubMed Central CAS Google Scholar Zhang, Y. E. Non-Smad pathways in TGF-beta signaling. Cell Res. 19, 128–139 (2009).Article PubMed PubMed Central CAS Google Scholar Jo, E., Park, S. J., Choi, Y. S., Jeon, W. K. & Kim, B. C. Kaempferol suppresses transforming growth factor-β1-induced epithelial-to-mesenchymal transition and migration of A549 lung cancer cells by inhibiting Akt1-mediated phosphorylation of Smad3 at threonine-179. Neoplasia 17, 525–537 (2015).Article PubMed PubMed Central CAS Google Scholar Remy, I., Montmarquette, A. & Michnick, S. W. PKB/Akt modulates TGF-beta signalling through a direct interaction with Smad3. Nat. Cell Biol. 6, 358–365 (2004).Article PubMed CAS Google Scholar Chen, J. et al. EGFR signaling promotes TGFβ-dependent renal fibrosis. J. Am. Soc. Nephrol. 23, 215–224 (2012).Article PubMed CAS Google Scholar Wang, S. E. et al. Oncogenic mutations regulate tumor microenvironment through induction of growth factors and angiogenic mediators. Oncogene 29, 3335–3348 (2010).Article PubMed PubMed Central CAS Google Scholar Wang, Z. et al. Activation of the BMP-BMPR pathway conferred resistance to EGFR-TKIs in lung squamous cell carcinoma patients with EGFR mutations. Proc. Natl. Acad. Sci. USA 112, 9990–9995 (2015).Article PubMed PubMed Central CAS Google Scholar Weng, T. et al. The MSP-RON pathway regulates liver fibrosis through transforming growth factor beta-dependent epithelial–mesenchymal transition. Liver Int. 41, 1956–1968 (2021).Article PubMed CAS Google Scholar Shi, Q. & Chen, Y. G. Interplay between TGF-β signaling and receptor tyrosine kinases in tumor development. Sci China Life Sci 60, 1133–1141 (2017).Article PubMed CAS Google Scholar Kreso, A. & Dick, J. E. Evolution of the cancer stem cell model. Cell Stem Cell 14, 275–291 (2014).Article PubMed CAS Google Scholar Prager, B. C., Xie, Q., Bao, S. & Rich, J. N. Cancer stem cells: the architects of the tumor ecosystem. Cell Stem Cell 24, 41–53 (2019).Article PubMed PubMed Central CAS Google Scholar Chen, J., Song, W. & Amato, K. Eph receptor tyrosine kinases in cancer stem cells. Cytokine Growth Factor Rev. 26, 1–6 (2015).Article PubMed Google Scholar Gao, M. et al. EGFR activates a TAZ-driven oncogenic program in glioblastoma. Cancer Res. 81, 3580–3592 (2021).Article PubMed PubMed Central CAS Google Scholar Nia, H. T., Munn, L. L. & Jain, R. K. Physical traits of cancer. Science 370, eaaz0868 (2020).Article PubMed PubMed Central CAS Google Scholar Sun, X. et al. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature 599, 673–678 (2021).Article PubMed PubMed Central CAS Google Scholar Xiong, Y. X. et al. Collagen I-DDR1 signaling promotes hepatocellular carcinoma cell stemness via Hippo signaling repression. Cell Death Differ. 30, 1648–1665 (2023).Article PubMed PubMed Central CAS Google Scholar Guan, X. et al. The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer. Cancer Commun. 39, 1 (2019).Article Google Scholar Debaugnies, M. et al. RHOJ controls EMT-associated resistance to chemotherapy. Nature 616, 168–175 (2023).Article PubMed PubMed Central CAS Google Scholar Murillo, M. M., del Castillo, G., Sánchez, A., Fernández, M. & Fabregat, I. Involvement of EGF receptor and c-Src in the survival signals induced by TGF-beta1 in hepatocytes. Oncogene 24, 4580–4587 (2005).Article PubMed CAS Google Scholar Wang, J. et al. PDGFR-α shRNA-polyplex for uveal melanoma treatment via EMT-mediated vasculogenic mimicry interfering. J. Nanobiotechnol. 22, 797 (2024).Article CAS Google Scholar Liu, X., Mei, W., Yao, Y. & Zeng, C. Current insights and barriers in FGFR-mediated signaling in lung cancer. Eur. J. Med. Chem. 296, 117897 (2025).Article PubMed CAS Google Scholar Antony, J. & Huang, R. Y. AXL-driven EMT state as a targetable conduit in cancer. Cancer Res. 77, 3725–3732 (2017).Article PubMed CAS Google Scholar Byers, L. A. et al. An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. Clin. Cancer Res. 19, 279–290 (2013).Article PubMed CAS Google Scholar De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).Article PubMed Google Scholar Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).Article PubMed CAS Google Scholar Lee, C. et al. Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives. Signal Transduct. Target Ther. 10, 170 (2025).Article PubMed PubMed Central CAS Google Scholar Guelfi, S., Hodivala-Dilke, K. & Bergers, G. Targeting the tumour vasculature: from vessel destruction to promotion. Nat. Rev. Cancer 24, 655–675 (2024).Article PubMed CAS Google Scholar Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P. & Griffioen, A. W. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540 (2021).Article PubMed Google Scholar Ozao-Choy, J. et al. The novel role of tyrosine kinase inhibitor in the reversal of immune suppression and modulation of tumor microenvironment for immune-based cancer therapies. Cancer Res. 69, 2514–2522 (2009).Article PubMed PubMed Central CAS Google Scholar Anderson, N. M. & Simon, M. C. The tumor microenvironment. Curr. Biol. 30, R921–R925 (2020).Article PubMed PubMed Central CAS Google Scholar Tang, Y., Zang, H., Wen, Q. & Fan, S. AXL in cancer: a modulator of drug resistance and therapeutic target. J. Exp. Clin. Cancer Res. 42, 148 (2023).Article PubMed PubMed Central CAS Google Scholar Cao, L. L. et al. Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling. Gut 72, 2038–2050 (2023).Article PubMed PubMed Central CAS Google Scholar Berestjuk, I. et al. Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma. EMBO Mol. Med. 14, e11814 (2022).Article PubMed CAS Google Scholar Cadamuro, M. et al. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J. Hepatol. 70, 700–709 (2019).Article PubMed CAS Google Scholar Martínez-Reyes, I. & Chandel, N. S. Cancer metabolism: looking forward. Nat. Rev. Cancer 21, 669–680 (2021).Article PubMed Google Scholar Liu, Y. et al. Metabolic reprogramming in tumor immune microenvironment: Impact on immune cell function and therapeutic implications. Cancer Lett. 597, 217076 (2024).Article PubMed CAS Google Scholar Jin, N. et al. Identification of metabolic vulnerabilities of receptor tyrosine kinases-driven cancer. Nat. Commun. 10, 2701 (2019).Article PubMed PubMed Central Google Scholar Zhong, C. et al. CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer. Nat. Commun. 15, 5502 (2024).Article PubMed PubMed Central CAS Google Scholar Wood, G. E., Hockings, H., Hilton, D. M. & Kermorgant, S. The role of MET in chemotherapy resistance. Oncogene 40, 1927–1941 (2021).Article PubMed PubMed Central CAS Google Scholar Fang, K. et al. Targeting IGF1R signaling enhances the sensitivity of cisplatin by inhibiting proline and arginine metabolism in oesophageal squamous cell carcinoma under hypoxia. J. Exp. Clin. Cancer Res. 42, 73 (2023).Article PubMed PubMed Central Google Scholar Hong, C. C. et al. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 268, 314–324 (2008).Article PubMed CAS Google Scholar Palisoul, M. L. et al. Inhibition of the receptor tyrosine kinase AXL restores paclitaxel chemosensitivity in uterine serous cancer. Mol. Cancer Ther. 16, 2881–2891 (2017).Article PubMed PubMed Central CAS Google Scholar Miles, D. H. et al. Discovery of AB801, a potent and selective inhibitor of AXL receptor tyrosine kinase for use in cancer therapy. J. Med. Chem. 68, 10663–10676 (2025).Article PubMed CAS Google Scholar Libby, P. Inflammation in atherosclerosis. Nature 420, 868–874 (2002).Article PubMed CAS Google Scholar Tu, L. et al. Targeted drug delivery systems for atherosclerosis. J. Nanobiotechnol. 23, 306 (2025).Article Google Scholar Zeboudj, L. et al. Selective EGF-receptor inhibition in CD4(+) T cells induces anergy and limits atherosclerosis. J. Am. Coll. Cardiol. 71, 160–172 (2018).Article PubMed CAS Google Scholar Waldmann, T. A. & Tagaya, Y. The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu. Rev. Immunol. 17, 19–49 (1999).Article PubMed CAS Google Scholar Finney, A. C. et al. EphA2 expression regulates inflammation and fibroproliferative remodeling in atherosclerosis. Circulation 136, 566–582 (2017).Article PubMed PubMed Central CAS Google Scholar Funk, S. D. & Orr, A. W. Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis. Pharmacol. Res. 67, 42–52 (2013).Article PubMed CAS Google Scholar Lu, C. et al. EphA2 blockage ALW-II-41-27 alleviates atherosclerosis by remodeling gut microbiota to regulate bile acid metabolism. NPJ Biofilms Microbiomes 10, 108 (2024).Article PubMed PubMed Central CAS Google Scholar Lin, Z. et al. Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice. Circulation 131, 1861–1871 (2015).Article PubMed PubMed Central CAS Google Scholar Zhang, C. J. et al. Wnt5a/Ror2 pathway contributes to the regulation of cholesterol homeostasis and inflammatory response in atherosclerosis. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1865, 158547 (2020).Article PubMed CAS Google Scholar Anisimov, A. et al. The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium. Nat. Cardiovasc. Res. 2, 307–321 (2023).Article PubMed PubMed Central CAS Google Scholar Woo, K. V. et al. Tie1 attenuation reduces murine atherosclerosis in a dose-dependent and shear stress-specific manner. J. Clin. Investig. 121, 1624–1635 (2011).Article PubMed PubMed Central Google Scholar Ma, C. N. et al. Targeting PDGF/PDGFR signaling pathway by microRNA, lncRNA, and circRNA for therapy of vascular diseases: a narrow review. Biomolecules 14, 1446 (2024).Article PubMed PubMed Central CAS Google Scholar Raines, E. W. PDGF and cardiovascular disease. Cytokine Growth Factor Rev. 15, 237–254 (2004).Article PubMed CAS Google Scholar Matsumoto, T. & Mugishima, H. Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis. J. Atheroscler. Thromb. 13, 130–135 (2006).Article PubMed CAS Google Scholar Sitbon, O. et al. Drugs targeting novel pathways in pulmonary arterial hypertension. Eur. Respir. J. 66, 2401830 (2025).Article PubMed CAS Google Scholar Hassoun, P. M. Pulmonary Arterial Hypertension. N. Engl. J. Med. 385, 2361–2376 (2021).Article PubMed CAS Google Scholar Wu, W. et al. Novel insights into receptor tyrosine kinases in pulmonary arterial hypertension. J. Am. Heart Assoc. 14, e042713 (2025).Article PubMed PubMed Central CAS Google Scholar Xiong, Y. et al. Receptor tyrosine kinase: still an interesting target to inhibit the proliferation of vascular smooth muscle cells. Am. J. Cardiovasc. Drugs 23, 497–518 (2023).Article PubMed Google Scholar Zhong, Y. & Yu, P. B. Angiogenesis redux: an overall protective role of VEGF/KDR signaling in the microvasculature in pulmonary arterial hypertension. Arterioscler. Thromb. Vasc. Biol. 43, 1784–1787 (2023).Article PubMed PubMed Central CAS Google Scholar Winter, M. P. et al. Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension. Basic Res. Cardiol. 115, 58 (2020).Article PubMed PubMed Central CAS Google Scholar Tuder, R. M. et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension: evidence for a process of disordered angiogenesis. J. Pathol. 195, 367–374 (2001).Article PubMed CAS Google Scholar Zhou, W. et al. Targeting VEGF-A/VEGFR2 Y949 signaling-mediated vascular permeability alleviates hypoxic pulmonary hypertension. Circulation 146, 1855–1881 (2022).Article PubMed CAS Google Scholar Xu, J. et al. Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis. J. Hypertens. 40, 1795–1807 (2022).Article PubMed PubMed Central Google Scholar Ghofrani, H. A., Gomberg-Maitland, M., Zhao, L. & Grimminger, F. Mechanisms and treatment of pulmonary arterial hypertension. Nat. Rev. Cardiol. 22, 105–120 (2025).Article PubMed Google Scholar Ghofrani, H. A. et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am. J. Respir. Crit. Care Med. 182, 1171–1177 (2010).Article PubMed PubMed Central CAS Google Scholar Frantz, R. P. et al. Seralutinib in adults with pulmonary arterial hypertension (TORREY): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Respir. Med. 12, 523–534 (2024).Article PubMed CAS Google Scholar Bian, J. S. et al. ErbB3 governs endothelial dysfunction in hypoxia-induced pulmonary hypertension. Circulation 150, 1533–1553 (2024).Article PubMed CAS Google Scholar Dahal, B. K. et al. Role of epidermal growth factor inhibition in experimental pulmonary hypertension. Am. J. Respir. Crit. Care Med. 181, 158–167 (2010).Article PubMed CAS Google Scholar Merklinger, S. L., Jones, P. L., Martinez, E. C. & Rabinovitch, M. Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension. Circulation 112, 423–431 (2005).Article PubMed CAS Google Scholar Saleby, J., Bouzina, H., Ahmed, S., Lundgren, J. & Radegran, G. Plasma receptor tyrosine kinase RET in pulmonary arterial hypertension diagnosis and differentiation. ERJ Open Res. 5, 00037-2019 (2019).Article PubMed PubMed Central Google Scholar Liang, M., Pang, Y., Zhang, S. & Zhang, M. Utility of hepatocyte growth factor as a biomarker for early diagnosis of pulmonary artery hypertension. Mol. Diagn. Ther. 20, 463–468 (2016).Article PubMed CAS Google Scholar Kümpers, P. et al. Circulating angiopoietins in idiopathic pulmonary arterial hypertension. Eur. Heart J. 31, 2291–2300 (2010).Article PubMed Google Scholar Fei, X. et al. Challenges and opportunities of developing small-molecule therapies for age-related macular degeneration. Arch. Pharm. Res. 47, 538–557 (2024).Article PubMed PubMed Central CAS Google Scholar Jaffe, G. J. et al. Dual antagonism of PDGF and VEGF in neovascular age-related macular degeneration: a phase IIb, multicenter, randomized controlled trial. Ophthalmology 124, 224–234 (2017).Article PubMed Google Scholar London, N. J. S. et al. Outcomes by faricimab treatment interval at week 48 of TENAYA-LUCERNE phase III trials in neovascular age-related macular degeneration. Ophthalmol. Retina 9, 1081–1089 (2025).Article PubMed Google Scholar Zhang, W. et al. Simultaneous inhibition of fibroblast growth factor-2 and vascular endothelial growth factor-a with RC28-E in diabetic macular edema: a phase 2 randomised trial. Br. J. Ophthalmol. 109, 784–790 (2025).Article PubMed Google Scholar Alli-Shaik, A. et al. System-wide vitreous proteome dissection reveals impaired sheddase activity in diabetic retinopathy. Theranostics 12, 6682–6704 (2022).Article PubMed PubMed Central CAS Google Scholar Heemels, M. T. Neurodegenerative diseases. Nature 539, 179 (2016).Article PubMed Google Scholar Ma, X. & Qiu, S. Control of cortical synapse development and plasticity by MET receptor tyrosine kinase, a genetic risk factor for autism. J. Neurosci. Res. 98, 2115–2129 (2020).Article PubMed CAS Google Scholar Christova, T., Ho, S. K., Liu, Y., Gill, M. & Attisano, L. LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity. EMBO Rep. 24, e56937 (2023).Article PubMed PubMed Central CAS Google Scholar Knopman, D. S. et al. Alzheimer disease. Nat. Rev. Dis. Primers 7, 33 (2021).Article PubMed PubMed Central Google Scholar Selkoe, D. J. Alzheimer’s disease. Cold Spring Harb. Perspect. Biol. 3, a004457 (2011).Article PubMed PubMed Central Google Scholar Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).Article PubMed PubMed Central CAS Google Scholar Bregman-Yemini, N., Nitzan, K., Franko, M. & Doron, R. Connecting the emotional-cognitive puzzle: the role of tyrosine kinase B (TrkB) receptor isoform imbalance in age-related emotional and cognitive impairments. Ageing Res. Rev. 99, 102349 (2024).Article PubMed CAS Google Scholar Massa, S. M. et al. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J. Clin. Investig. 120, 1774–1785 (2010).Article PubMed PubMed Central CAS Google Scholar Lao-Peregrin, C. et al. Synaptic plasticity via receptor tyrosine kinase/G-protein-coupled receptor crosstalk. Cell Rep. 43, 113595 (2024).Article PubMed CAS Google Scholar Ishii, M. & Iadecola, C. Risk factor for Alzheimer’s disease breaks the blood-brain barrier. Nature 581, 31–32 (2020).Article PubMed PubMed Central CAS Google Scholar Fu, X., Wang, J., Cai, H., Jiang, H. & Han, S. C16 peptide and Ang-1 improve functional disability and pathological changes in an Alzheimer’s disease model associated with vascular dysfunction. Pharmaceuticals 15, 471 (2022).Article PubMed PubMed Central CAS Google Scholar Wang, M. et al. Novel genes involved in vascular dysfunction of the middle temporal gyrus in Alzheimer’s disease: transcriptomics combined with machine learning analysis. Neural Regen. Res. 20, 3620–3634 (2025).Article PubMed CAS Google Scholar Cissé, M. et al. Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47–52 (2011).Article PubMed Google Scholar Fu, A. K. et al. Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 111, 9959–9964 (2014).Article PubMed PubMed Central CAS Google Scholar Matsumoto, M., Gomez-Soler, M., Lombardi, S., Lechtenberg, B. C. & Pasquale, E. B. Missense mutations of the ephrin receptor EPHA1 associated with Alzheimer’s disease disrupt receptor signaling functions. J. Biol. Chem. 301, 108099 (2025).Article PubMed CAS Google Scholar Phan, L. et al. Parkinson’s paradox: alpha-synuclein’s selective strike on SNc dopamine neurons over VTA. NPJ Parkinsons Dis. 11, 207 (2025).Article PubMed PubMed Central CAS Google Scholar Lang, A. E. & Espay, A. J. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov. Disord. 33, 660–677 (2018).Article PubMed Google Scholar Hyman, C. et al. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350, 230–232 (1991).Article PubMed CAS Google Scholar Howells, D. W. et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp. Neurol. 166, 127–135 (2000).Article PubMed CAS Google Scholar Scalzo, P., Kümmer, A., Bretas, T. L., Cardoso, F. & Teixeira, A. L. Serum levels of brain-derived neurotrophic factor correlate with motor impairment in Parkinson’s disease. J. Neurol. 257, 540–545 (2010).Article PubMed CAS Google Scholar Kang, S. S. et al. TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease. Proc. Natl. Acad. Sci. USA 114, 10773–10778 (2017).Article PubMed PubMed Central CAS Google Scholar Kopra, J. J. et al. Dampened amphetamine-stimulated behavior and altered dopamine transporter function in the absence of brain GDNF. J. Neurosci. 37, 1581–1590 (2017).Article PubMed PubMed Central CAS Google Scholar Conway, J. A. & Kramer, E. R. Is activation of GDNF/RET signaling the answer for successful treatment of Parkinson’s disease? A discussion of data from the culture dish to the clinic. Neural Regen Res. 17, 1462–1467 (2022).Article PubMed PubMed Central CAS Google Scholar Decressac, M. et al. GDNF fails to exert neuroprotection in a rat α-synuclein model of Parkinson’s disease. Brain 134, 2302–2311 (2011).Article PubMed Google Scholar Chmielarz, P. et al. GDNF/RET signaling pathway activation eliminates lewy body pathology in midbrain dopamine neurons. Mov. Disord. 35, 2279–2289 (2020).Article PubMed CAS Google Scholar Whone, A. et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain 142, 512–525 (2019).Article PubMed PubMed Central Google Scholar Brown, R. H. & Al-Chalabi, A. Amyotrophic Lateral Sclerosis. N. Engl. J. Med. 377, 162–172 (2017).Article PubMed CAS Google Scholar Mora, J. S. et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph. Lateral Scler Frontotemporal Degener. 21, 5–14 (2020).Article PubMed CAS Google Scholar Sufit, R. L., Ajroud-Driss, S., Casey, P. & Kessler, J. A. Open label study to assess the safety of VM202 in subjects with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler Frontotemporal Degener. 18, 269–278 (2017).Article PubMed CAS Google Scholar Trias, E. et al. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J. Neuroinflammation 13, 177 (2016).Article PubMed PubMed Central Google Scholar Kovacs, M. et al. The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS. Acta Neuropathol. Commun. 9, 136 (2021).Article PubMed PubMed Central CAS Google Scholar Dennys, C. et al. EphA4 targeting agents protect motor neurons from cell death induced by amyotrophic lateral sclerosis-astrocytes. iScience 25, 104877 (2022).Article PubMed PubMed Central CAS Google Scholar Takahashi, Y. et al. ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am. J. Hum. Genet. 93, 900–905 (2013).Article PubMed PubMed Central CAS Google Scholar Kwon, Y. et al. Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS). J. Neurol. Sci. 457, 122885 (2024).Article PubMed CAS Google Scholar Amirabadizadeh, A. et al. Exploring the bidirectional association between thyrotropin and thyroid hormones in type 2 diabetes: a systematic review and meta-analysis. J. Diabetes Metab. Disord. 24, 98 (2025).Article PubMed PubMed Central CAS Google Scholar UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837–853 (1998).Fountas, A., Diamantopoulos, L. N. & Tsatsoulis, A. Tyrosine kinase inhibitors and diabetes: a novel treatment paradigm? Trends Endocrinol. Metab. 26, 643–656 (2015).Article PubMed CAS Google Scholar Gitelman, S. E. et al. Imatinib therapy for patients with recent-onset type 1 diabetes: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Diabetes Endocrinol 9, 502–514 (2021).Article PubMed PubMed Central CAS Google Scholar Accili, D., Deng, Z. & Liu, Q. Insulin resistance in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 21, 413–426 (2025).Article PubMed CAS Google Scholar Agudo, J. et al. Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of β-cell mass. Diabetes 61, 2851–2861 (2012).Article PubMed PubMed Central CAS Google Scholar Mukai, E. et al. Enhanced vascular endothelial growth factor signaling in islets contributes to β cell injury and consequential diabetes in spontaneously diabetic Torii rats. Diabetes Res. Clin. Pract. 106, 303–311 (2014).Article PubMed CAS Google Scholar Villalta, S. A. et al. Inhibition of VEGFR-2 reverses type 1 diabetes in NOD mice by abrogating insulitis and restoring islet function. Diabetes 62, 2870–2878 (2013).Article PubMed PubMed Central CAS Google Scholar Lammert, E. et al. Role of VEGF-A in vascularization of pancreatic islets. Curr. Biol. 13, 1070–1074 (2003).Article PubMed CAS Google Scholar Itani, S. I., Ruderman, N. B., Schmieder, F. & Boden, G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51, 2005–2011 (2002).Article PubMed CAS Google Scholar Liu, X. et al. Insulin induces insulin receptor degradation in the liver through EphB4. Nat. Metab. 4, 1202–1213 (2022).Article PubMed CAS Google Scholar Li, Z. et al. Inhibition of epidermal growth factor receptor activation is associated with improved diabetic nephropathy and insulin resistance in type 2 diabetes. Diabetes 67, 1847–1857 (2018).Article PubMed PubMed Central CAS Google Scholar Abderrahmani, A. et al. Increased hepatic PDGF-AA signaling mediates liver insulin resistance in obesity-associated type 2 diabetes. Diabetes 67, 1310–1321 (2018).Article PubMed CAS Google Scholar Yuasa, T. et al. Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing platelet-derived growth factor receptor in the muscle, but it does not affect blood glucose levels. Diabetes 53, 2776–2786 (2004).Article PubMed CAS Google Scholar Fafalios, A. et al. A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nat. Med. 17, 1577–1584 (2011).Article PubMed PubMed Central CAS Google Scholar Foltz, I. N. et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci. Transl. Med. 4, 162ra153 (2012).Article PubMed Google Scholar Zhang, X. et al. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 57, 1246–1253 (2008).Article PubMed CAS Google Scholar Morton, G. J. et al. FGF19 action in the brain induces insulin-independent glucose lowering. J. Clin. Investig. 123, 4799–4808 (2013).Article PubMed PubMed Central CAS Google Scholar Tomlinson, E. et al. Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity. Endocrinology 143, 1741–1747 (2002).Article PubMed CAS Google Scholar Kir, S. et al. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science 331, 1621–1624 (2011).Article PubMed PubMed Central CAS Google Scholar Li, J. et al. The global prevalence and impact of steatotic liver disease and viral infections: a systematic review and meta-analysis. Hepatol. Commun. 9, e0689 (2025).Article PubMed PubMed Central Google Scholar Bhushan, B. et al. Pharmacologic inhibition of epidermal growth factor receptor suppresses nonalcoholic fatty liver disease in a murine fast-food diet model. Hepatology 70, 1546–1563 (2019).Article PubMed CAS Google Scholar Bagchi, M. et al. Vascular endothelial growth factor is important for brown adipose tissue development and maintenance. FASEB J 27, 3257–3271 (2013).Article PubMed PubMed Central CAS Google Scholar Cai, B. et al. Macrophage MerTK promotes liver fibrosis in nonalcoholic steatohepatitis. Cell Metab. 31, 406–421.e7 (2020).Article PubMed CAS Google Scholar Lijnen, H. R., Christiaens, V. & Scroyen, L. Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice. J. Pharmacol. Exp. Ther. 337, 457–464 (2011).Article PubMed CAS Google Scholar Tutusaus, A. et al. A Functional Role of GAS6/TAM in nonalcoholic steatohepatitis progression implicates AXL as therapeutic target. Cell. Mol. Gastroenterol. Hepatol. 9, 349–368 (2020).Article PubMed Google Scholar Pridans, C. et al. Macrophage colony-stimulating factor increases hepatic macrophage content, liver growth, and lipid accumulation in neonatal rats. Am. J. Physiol. Gastrointest. Liver Physiol. 314, G388–G398 (2018).Article PubMed Google Scholar Sun, C., Berry, W. L. & Olson, L. E. PDGFRα controls the balance of stromal and adipogenic cells during adipose tissue organogenesis. Development 144, 83–94 (2017).Article PubMed PubMed Central CAS Google Scholar Guo, L. et al. Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression. J. Clin. Investig. 127, 4449–4461 (2017).Article PubMed PubMed Central Google Scholar Chen, Z. et al. Nrg4 promotes fuel oxidation and a healthy adipokine profile to ameliorate diet-induced metabolic disorders. Mol. Metab. 6, 863–872 (2017).Article PubMed PubMed Central CAS Google Scholar Wang, G. X. et al. The brown fat-enriched secreted factor Nrg4 preserves metabolic homeostasis through attenuation of hepatic lipogenesis. Nat. Med. 20, 1436–1443 (2014).Article PubMed PubMed Central CAS Google Scholar Tahara, M., Matsumoto, K., Nukiwa, T. & Nakamura, T. Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats. J. Clin. Investig. 103, 313–320 (1999).Article PubMed PubMed Central CAS Google Scholar Kosone, T. et al. HGF ameliorates a high-fat diet-induced fatty liver. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G204–G210 (2007).Article PubMed CAS Google Scholar Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).Article PubMed CAS Google Scholar Pisetsky, D. S. Pathogenesis of autoimmune disease. Nat. Rev. Nephrol. 19, 509–524 (2023).Article PubMed PubMed Central CAS Google Scholar Fugger, L., Jensen, L. T. & Rossjohn, J. Challenges, progress, and prospects of developing therapies to treat autoimmune diseases. Cell 181, 63–80 (2020).Article PubMed CAS Google Scholar Ramírez-Valle, F., Maranville, J. C., Roy, S. & Plenge, R. M. Sequential immunotherapy: towards cures for autoimmunity. Nat. Rev. Drug Discov. 23, 501–524 (2024).Article PubMed Google Scholar Smolen, J. S., Aletaha, D. & McInnes, I. B. Rheumatoid arthritis. Lancet 388, 2023–2038 (2016).Article PubMed CAS Google Scholar Gao, L. et al. Receptor tyrosine kinases Tyro3, Axl, and Mertk differentially contribute to antibody-induced arthritis. Cell Commun. Signal. 21, 195 (2023).Article PubMed PubMed Central CAS Google Scholar Bassyouni, I. H., El-Wakd, M. M., Azab, N. A. & Bassyouni, R. H. Diminished soluble levels of growth arrest specific protein 6 and tyrosine kinase receptor Axl in patients with rheumatoid arthritis. Int. J. Rheum. Dis. 20, 53–59 (2017).Article PubMed CAS Google Scholar Kurowska-Stolarska, M. et al. MicroRNA-34a dependent regulation of AXL controls the activation of dendritic cells in inflammatory arthritis. Nat. Commun. 8, 15877 (2017).Article PubMed PubMed Central CAS Google Scholar Waterborg, C. E. J. et al. Protective role of the MER tyrosine kinase via efferocytosis in rheumatoid arthritis models. Front. Immunol. 9, 742 (2018).Article PubMed PubMed Central Google Scholar Ruiz-Heiland, G. et al. Deletion of the receptor tyrosine kinase Tyro3 inhibits synovial hyperplasia and bone damage in arthritis. Ann. Rheum. Dis. 73, 771–779 (2014).Article PubMed CAS Google Scholar Wang, Z. et al. Tyro3 receptor tyrosine kinase contributes to pathogenic phenotypes of fibroblast-like synoviocytes in rheumatoid arthritis and disturbs immune cell balance in experimental arthritis. Clin. Immunol. 255, 109753 (2023).Article PubMed CAS Google Scholar Xue, J. et al. CD14(+)CD16(-) monocytes are the main precursors of osteoclasts in rheumatoid arthritis via expressing Tyro3TK. Arthritis Res. Ther. 22, 221 (2020).Article PubMed PubMed Central CAS Google Scholar Charbonneau, M. et al. Platelet-derived growth factor receptor activation promotes the prodestructive invadosome-forming phenotype of synoviocytes from patients with rheumatoid arthritis. J. Immunol. 196, 3264–3275 (2016).Article PubMed CAS Google Scholar Laragione, T. et al. Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling. Ann. Rheum. Dis. 77, 1627–1635 (2018).Article PubMed CAS Google Scholar Rosengren, S., Corr, M. & Boyle, D. L. Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes. Arthritis Res. Ther. 12, R65 (2010).Article PubMed PubMed Central Google Scholar Paniagua, R. T. et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J. Clin. Investig. 116, 2633–2642 (2006).Article PubMed PubMed Central CAS Google Scholar Eklund, K. K. et al. Maintained efficacy of the tyrosine kinase inhibitor imatinib mesylate in a patient with rheumatoid arthritis. J. Clin. Rheumatol. 14, 294–296 (2008).Article PubMed Google Scholar Eklund, K. K. & Joensuu, H. Treatment of rheumatoid arthritis with imatinib mesylate: clinical improvement in three refractory cases. Ann. Med. 35, 362–367 (2003).Article PubMed CAS Google Scholar Miyachi, K. et al. Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia. Clin. Rheumatol. 22, 329–332 (2003).Article PubMed CAS Google Scholar Druker, B. J. et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N. Engl. J. Med. 355, 2408–2417 (2006).Article PubMed CAS Google Scholar Egal, E. S. A. et al. EphB2 receptor promotes dermal fibrosis in systemic sclerosis. Arthritis Rheumatol. 76, 1303–1316 (2024).Article PubMed PubMed Central CAS Google Scholar Gerlicz, Z., Dziankowska-Bartkowiak, B., Dziankowska-Zaborszczyk, E. & Sysa-Jedrzejowska, A. Disturbed balance between serum levels of receptor tyrosine Kinases Tie-1, Tie-2 and angiopoietins in systemic sclerosis. Dermatology 228, 233–239 (2014).Article PubMed CAS Google Scholar Carvalheiro, T. et al. Angiopoietin-2 promotes inflammatory activation in monocytes of systemic sclerosis patients. Int. J. Mol. Sci. 21, 1–10 (2020).Article Google Scholar Gheita, T. A., Bassyouni, I. H. & Bassyouni, R. H. Plasma concentrations of growth arrest specific protein 6 and the soluble form of its tyrosine kinase receptor Axl in patients with Systemic lupus erythematosus and Behçets disease. J. Clin. Immunol. 32, 1279–1286 (2012).Article PubMed CAS Google Scholar Rothlin, C. V. & Lemke, G. TAM receptor signaling and autoimmune disease. Curr. Opin. Immunol. 22, 740–746 (2010).Article PubMed PubMed Central CAS Google Scholar Lou, H., Ling, G. S. & Cao, X. Autoantibodies in systemic lupus erythematosus: From immunopathology to therapeutic target. J. Autoimmun. 132, 102861 (2022).Article PubMed CAS Google Scholar Siegel, C. H. & Sammaritano, L. R. Systemic lupus erythematosus: a review. JAMA 331, 1480–1491 (2024).Article PubMed CAS Google Scholar Bellan, M. et al. Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis. Clin. Exp. Rheumatol. 39, 132–138 (2021).Article PubMed Google Scholar Gong, S. et al. Plasma sMer, sAxl and GAS6 levels correlate with disease activity and severity in lupus nephritis. Eur. J. Clin. Investig. 49, e13064 (2019).Article Google Scholar Henderson, N. C., Rieder, F. & Wynn, T. A. Fibrosis: from mechanisms to medicines. Nature 587, 555–566 (2020).Article PubMed PubMed Central CAS Google Scholar Hammerich, L. & Tacke, F. Hepatic inflammatory responses in liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 20, 633–646 (2023).Article PubMed CAS Google Scholar Trivedi, P., Wang, S. & Friedman, S. L. The power of plasticity-metabolic regulation of hepatic stellate cells. Cell Metab. 33, 242–257 (2021).Article PubMed CAS Google Scholar Bárcena, C. et al. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J. Hepatol. 63, 670–678 (2015).Article PubMed PubMed Central Google Scholar Staufer, K. et al. Gas6 in chronic liver disease—a novel blood-based biomarker for liver fibrosis. Cell Death Discov 9, 282 (2023).Article PubMed PubMed Central CAS Google Scholar Bano, S. et al. Hepatocyte-speciFic Epidermal Growth Factor Receptor Deletion Promotes Fibrosis But Has No Effect On Steatosis In Fast-food Diet Model Of Metabolic Dysfunction-associated Steatotic Liver Disease. Cell. Mol. Gastroenterol. Hepatol. 18, 101380 (2024).Article PubMed PubMed Central CAS Google Scholar Thannickal, V. J., Toews, G. B., White, E. S., Lynch, J. P. 3rd & Martinez, F. J. Mechanisms of pulmonary fibrosis. Annu. Rev. Med. 55, 395–417 (2004).Article PubMed CAS Google Scholar Richeldi, L., Collard, H. R. & Jones, M. G. Idiopathic pulmonary fibrosis. Lancet 389, 1941–1952 (2017).Article PubMed Google Scholar Avivi-Green, C., Singal, M. & Vogel, W. F. Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis. Am. J. Respir. Crit. Care Med. 174, 420–427 (2006).Article PubMed CAS Google Scholar Jia, S. et al. Discoidin Domain Receptor 2 Signaling Regulates Fibroblast Apoptosis Through PDK1/Akt. Am. J. Respir. Cell Mol. Biol. 59, 295–305 (2018).Article PubMed PubMed Central CAS Google Scholar Zhao, H. et al. Targeting of discoidin domain receptor 2 (DDR2) prevents myofibroblast activation and neovessel formation during pulmonary fibrosis. Mol. Ther. 24, 1734–1744 (2016).Article PubMed PubMed Central CAS Google Scholar Cherubini, E. et al. BDNF/TrkB axis activation promotes epithelial-mesenchymal transition in idiopathic pulmonary fibrosis. J. Transl. Med. 15, 196 (2017).Article PubMed PubMed Central Google Scholar Freeman, M. R. et al. Brain-derived neurotrophic factor and airway fibrosis in asthma. Am. J. Physiol. Lung Cell Mol. Physiol. 313, L360–L370 (2017).Article PubMed PubMed Central Google Scholar Hohmann, M. S. et al. Antibody-mediated depletion of CCR10+EphA3+ cells ameliorates fibrosis in IPF. JCI Insight 6, e141061 (2021).Article PubMed PubMed Central Google Scholar Ou, X. M. et al. VEGFR-2 antagonist SU5416 attenuates bleomycin-induced pulmonary fibrosis in mice. Int. Immunopharmacol. 9, 70–79 (2009).Article PubMed CAS Google Scholar Richeldi, L. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 370, 2071–2082 (2014).Article PubMed Google Scholar Espindola, M. S. et al. Targeting of TAM receptors ameliorates fibrotic mechanisms in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 197, 1443–1456 (2018).Article PubMed PubMed Central CAS Google Scholar Lee, Y. J., Kim, M., Kim, H. S. & Kang, J. L. Administration of Gas6 attenuates lung fibrosis via inhibition of the epithelial-mesenchymal transition and fibroblast activation. Cell Biol. Toxicol. 40, 20 (2024).Article PubMed PubMed Central CAS Google Scholar Liu, Q. et al. Gas6-Axl signal promotes indoor VOCs exposure-induced pulmonary fibrosis via pulmonary microvascular endothelial cells-fibroblasts cross-talk. J. Hazard. Mater. 474, 134786 (2024).Article PubMed CAS Google Scholar Yang, D. C. et al. Targeting the AXL receptor in combating smoking-related pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 64, 734–746 (2021).Article PubMed PubMed Central CAS Google Scholar Liu, M., López de Juan Abad, B. & Cheng, K. Cardiac fibrosis: myofibroblast-mediated pathological regulation and drug delivery strategies. Adv. Drug Deliv. Rev. 173, 504–519 (2021).Article PubMed PubMed Central CAS Google Scholar Kong, P., Christia, P. & Frangogiannis, N. G. The pathogenesis of cardiac fibrosis. Cell. Mol. Life Sci. 71, 549–574 (2014).Article PubMed CAS Google Scholar Zhao, Y. F. et al. Growth arrest-specific 6 exacerbates pressure overload-induced cardiac hypertrophy. Hypertension 67, 118–129 (2016).Article PubMed CAS Google Scholar George, M., Vijayakumar, A., Dhanesh, S. B., James, J. & Shivakumar, K. Molecular basis and functional significance of Angiotensin II-induced increase in Discoidin Domain Receptor 2 gene expression in cardiac fibroblasts. J. Mol. Cell. Cardiol. 90, 59–69 (2016).Article PubMed CAS Google Scholar Titus, A. S. et al. Metformin attenuates hyperglycaemia-stimulated pro-fibrotic gene expression in adventitial fibroblasts via inhibition of discoidin domain receptor 2. Int. J. Mol. Sci. 24, 585 (2023).Article CAS Google Scholar Chavkin, N. W. et al. The cell surface receptors Ror1/2 control cardiac myofibroblast differentiation. J. Am. Heart Assoc. 10, e019904 (2021).Article PubMed PubMed Central CAS Google Scholar Huang, Z. et al. Key role for EphB2 receptor in kidney fibrosis. Clin. Sci. 135, 2127–2142 (2021).Article CAS Google Scholar Borza, C. M. et al. DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3. JCI Insight 7, e150887 (2022).Article PubMed PubMed Central Google Scholar Flamant, M. et al. Discoidin domain receptor 1 null mice are protected against hypertension-induced renal disease. J. Am. Soc. Nephrol. 17, 3374–3381 (2006).Article PubMed CAS Google Scholar Yoshimoto, H. et al. Overexpression of insulin-like growth factor-1 (IGF-I) receptor and the invasiveness of cultured keloid fibroblasts. Am. J. Pathol. 154, 883–889 (1999).Article PubMed PubMed Central CAS Google Scholar Inoue, Y. et al. Real-world safety, tolerability and effectiveness of nintedanib in patients with idiopathic pulmonary fibrosis: final report of post-marketing surveillance in Japan. Adv. Ther. 42, 1075–1093 (2025).Article PubMed CAS Google Scholar Shimojima, M. et al. Tyro3 family-mediated cell entry of Ebola and Marburg viruses. J. Virol. 80, 10109–10116 (2006).Article PubMed PubMed Central CAS Google Scholar Bekerman, E. & Einav, S. Infectious disease. Combating emerging viral threats. Science 348, 282–283 (2015).Article PubMed PubMed Central CAS Google Scholar Eierhoff, T., Hrincius, E. R., Rescher, U., Ludwig, S. & Ehrhardt, C. The epidermal growth factor receptor (EGFR) promotes uptake of influenza A viruses (IAV) into host cells. PLoS Pathog. 6, e1001099 (2010).Article PubMed PubMed Central Google Scholar Verma, V. et al. Influenza A virus activates cellular Tropomyosin receptor kinase A (TrkA) signaling to promote viral replication and lung inflammation. PLoS Pathog. 18, e1010874 (2022).Article PubMed PubMed Central CAS Google Scholar Ueki, I. F. et al. Respiratory virus-induced EGFR activation suppresses IRF1-dependent interferon λ and antiviral defense in airway epithelium. J. Exp. Med. 210, 1929–1936 (2013).Article PubMed PubMed Central CAS Google Scholar Shin, H. J. et al. SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation. Signal Transduct. Target Ther. 9, 125 (2024).Article PubMed PubMed Central CAS Google Scholar Wang, S. et al. AXL is a candidate receptor for SARS-CoV-2 that promotes infection of pulmonary and bronchial epithelial cells. Cell Res. 31, 126–140 (2021).Article PubMed PubMed Central CAS Google Scholar Lupberger, J. et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat. Med. 17, 589–595 (2011).Article PubMed PubMed Central CAS Google Scholar Wood, N. J. Hepatitis C: Host receptor tyrosine kinases mediate HCV entry and are a promising new target for antiviral therapy. Nat. Rev. Gastroenterol. Hepatol. 8, 361 (2011).Article PubMed Google Scholar Pan, Q. et al. EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses. Nat. Commun. 15, 652 (2024).Article PubMed PubMed Central CAS Google Scholar Saviano, A. et al. Safety and antiviral activity of EGFR inhibition by erlotinib in chronic hepatitis C patients: a phase ib randomized controlled trial. Clin. Transl. Gastroenterol. 13, e00492 (2022).Article PubMed PubMed Central Google Scholar Jeon, S. et al. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. Antimicrob. Agents Chemother. 64, e00819-20 (2020).Article PubMed PubMed Central Google Scholar Stewart, C. M. et al. Ebola virus triggers receptor tyrosine kinase-dependent signaling to promote the delivery of viral particles to entry-conducive intracellular compartments. PLoS Pathog. 17, e1009275 (2021).Article PubMed PubMed Central CAS Google Scholar Watanabe, K. et al. The whole picture of first-line osimertinib for EGFR mutation-positive advanced NSCLC: real-world efficacy, safety, progression pattern, and posttreatment therapy (Reiwa Study). JTO Clin. Res. Rep. 5, 100720 (2024).PubMed PubMed Central Google Scholar Montor, W. R., Salas, A. & Melo, F. H. M. Receptor tyrosine kinases and downstream pathways as druggable targets for cancer treatment: the current arsenal of inhibitors. Mol. Cancer 17, 55 (2018).Article PubMed PubMed Central Google Scholar Suda, K. et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J. Thorac. Oncol. 6, 1152–1161 (2011).Article PubMed Google Scholar Wu, D. et al. Acquired resistance to tyrosine kinase targeted therapy: mechanism and tackling strategies. Drug Resist. Updat. 78, 101176 (2025).Article PubMed CAS Google Scholar Curigliano, G. et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann. Oncol. 31, 171–190 (2020).Article PubMed PubMed Central CAS Google Scholar Yang, C. et al. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 20, 203–222 (2023).Article PubMed Google Scholar Zhao, S. et al. Clinical research progress of fruquintinib in the treatment of malignant tumors. Invest. New Drugs 42, 612–622 (2024).Article PubMed PubMed Central CAS Google Scholar Jia, Y. et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534, 129–132 (2016).Article PubMed PubMed Central CAS Google Scholar Hussain, S., Mursal, M., Verma, G., Hasan, S. M. & Khan, M. F. Targeting oncogenic kinases: Insights on FDA approved tyrosine kinase inhibitors. Eur. J. Pharmacol. 970, 176484 (2024).Article PubMed CAS Google Scholar Golay, J. & Introna, M. Mechanism of action of therapeutic monoclonal antibodies: promises and pitfalls of in vitro and in vivo assays. Arch. Biochem. Biophys. 526, 146–153 (2012).Article PubMed CAS Google Scholar Shim, H. Bispecific antibodies and antibody-drug conjugates for cancer therapy: technological considerations. Biomolecules 10, 360 (2020).Article PubMed PubMed Central CAS Google Scholar Arnoletti, J. P. et al. Mechanisms of resistance to Erbitux (anti-epidermal growth factor receptor) combination therapy in pancreatic adenocarcinoma cells. J. Gastrointest. Surg. 8, 960–969 (2004). discussion 969-970.Article PubMed Google Scholar Li, H., Er Saw, P. & Song, E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell. Mol. Immunol. 17, 451–461 (2020).Article PubMed PubMed Central CAS Google Scholar Feng, L. et al. Biological evaluation of antibody-maytansinoid conjugates as a strategy of RON targeted drug delivery for treatment of non-small cell lung cancer. J. Exp. Clin. Cancer Res. 35, 70 (2016).Article PubMed PubMed Central Google Scholar Wang, M. et al. Humanized dual-targeting antibody-drug conjugates specific to MET and RON receptors as a pharmaceutical strategy for the treatment of cancers exhibiting phenotypic heterogeneity. Acta Pharmacol. Sin. 46, 1375–1389 (2025).Article PubMed PubMed Central CAS Google Scholar Cui, X. et al. A novel bispecific antibody targeting PD-L1 and VEGF with combined anti-tumor activities. Front. Immunol. 12, 778978 (2021).Article PubMed PubMed Central CAS Google Scholar Ridgway, J. B., Presta, L. G. & Carter, P. Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng 9, 617–621 (1996).Article PubMed CAS Google Scholar Schaefer, W. et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc. Natl. Acad. Sci. USA 108, 11187–11192 (2011).Article PubMed PubMed Central CAS Google Scholar Thakur, A., Huang, M. & Lum, L. G. Bispecific antibody-based therapeutics: strengths and challenges. Blood Rev. 32, 339–347 (2018).Article PubMed CAS Google Scholar Zhao, P. et al. Recent advances of antibody drug conjugates for clinical applications. Acta Pharm. Sin. B 10, 1589–1600 (2020).Article PubMed PubMed Central CAS Google Scholar Sievers, E. L. & Senter, P. D. Antibody-drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15–29 (2013).Article PubMed CAS Google Scholar Lambert, J. M. & Berkenblit, A. Antibody-drug conjugates for cancer treatment. Annu. Rev. Med. 69, 191–207 (2018).Article PubMed CAS Google Scholar Lambert, J. M. & Chari, R. V. Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J. Med. Chem. 57, 6949–6964 (2014).Article PubMed CAS Google Scholar Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791 (2012).Article PubMed PubMed Central CAS Google Scholar Tarantino, P. et al. Antibody-drug conjugates: Smart chemotherapy delivery across tumor histologies. CA Cancer J. Clin. 72, 165–182 (2022).PubMed Google Scholar Modi, S. et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N. Engl. J. Med. 382, 610–621 (2020).Article PubMed CAS Google Scholar Diéras, V. et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 18, 732–742 (2017).Article PubMed PubMed Central Google Scholar Schettini, F. et al. Identification of cell surface targets for CAR-T cell therapies and antibody-drug conjugates in breast cancer. ESMO Open 6, 100102 (2021).Article PubMed PubMed Central CAS Google Scholar Whalen, K. A. et al. Targeting the somatostatin receptor 2 with the miniaturized drug conjugate, PEN-221: a potent and novel therapeutic for the treatment of small cell lung cancer. Mol. Cancer Ther. 18, 1926–1936 (2019).Article PubMed CAS Google Scholar Cazes, A. et al. A MET targeting antibody-drug conjugate overcomes gemcitabine resistance in pancreatic cancer. Clin. Cancer Res. 27, 2100–2110 (2021).Article PubMed CAS Google Scholar Zammarchi, F. et al. Preclinical development of ADCT-601, a novel pyrrolobenzodiazepine dimer-based antibody-drug conjugate targeting AXL-expressing cancers. Mol. Cancer Ther. 21, 582–593 (2022).Article PubMed PubMed Central CAS Google Scholar Yao, H. P. et al. Therapeutic efficacy, pharmacokinetic profiles, and toxicological activities of humanized antibody-drug conjugate Zt/g4-MMAE targeting RON receptor tyrosine kinase for cancer therapy. J. Immunother. Cancer 7, 75 (2019).Article PubMed PubMed Central Google Scholar Tong, X. M. et al. Therapeutic efficacy of a novel humanized antibody-drug conjugate recognizing plexin-semaphorin-integrin domain in the RON receptor for targeted cancer therapy. J. Immunother. Cancer 7, 250 (2019).Article PubMed PubMed Central Google Scholar Flynn, P., Suryaprakash, S., Grossman, D., Panier, V. & Wu, J. The antibody-drug conjugate landscape. Nat. Rev. Drug Discov. 23, 577–578 (2024).Article PubMed CAS Google Scholar Nakagawa, K. et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 20, 1655–1669 (2019).Article PubMed CAS Google Scholar Naumov, G. N. et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin. Cancer Res. 15, 3484–3494 (2009).Article PubMed PubMed Central CAS Google Scholar Motzer, R. J. et al. Kidney Cancer, Version 3.2022, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw. 20, 71–90 (2022).Article PubMed PubMed Central Google Scholar Gorin, M. A. et al. Neoadjuvant nivolumab in patients with high-risk nonmetastatic renal cell carcinoma. Eur. Urol. Oncol. 5, 113–117 (2022).Article PubMed Google Scholar Carlo, M. I. et al. Phase II study of neoadjuvant nivolumab in patients with locally advanced clear cell renal cell carcinoma undergoing nephrectomy. Eur. Urol. 81, 570–573 (2022).Article PubMed PubMed Central CAS Google Scholar Bex, A. et al. Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx). J. Clin. Oncol. 40, 289–289 (2022).Article Google Scholar Huang, J. et al. Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial. J. Immunother. Cancer 12, e008475 (2024).Article PubMed PubMed Central Google Scholar Lee, C. K. et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol 4, 210–216 (2018).Article PubMed PubMed Central Google Scholar Yang, J. C. et al. Phase III KEYNOTE-789 study of pemetrexed and platinum with or without pembrolizumab for tyrosine kinase inhibitor‒resistant, EGFR-mutant, metastatic nonsquamous non-small cell lung cancer. J. Clin. Oncol. 42, 4029–4039 (2024).Article PubMed PubMed Central CAS Google Scholar Malam, Y., Loizidou, M. & Seifalian, A. M. Liposomes and nanoparticles: nanosized vehicles for drug delivery in cancer. Trends Pharmacol. Sci. 30, 592–599 (2009).Article PubMed CAS Google Scholar Juul, C. A. et al. HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model. J. Control. Release 371, 288–297 (2024).Article PubMed CAS Google Scholar Zhang, J., Li, X., Yin, Y., Cao, G. & Wang, H. A Biodegradable nucleotide coordination polymer for enhanced NSCLC therapy in combination with metabolic modulation. Adv. Healthc. Mater. 12, e2302187 (2023).Article PubMed Google Scholar Papa, S. et al. A phase I trial of T4 CAR T-cell immunotherapy in head and neck squamous cancer (HNSCC). J. Clin. Oncol. 36, 3046–3046 (2018).Article Google Scholar Lin, C. & Zhang, J. Chimeric antigen receptor engineered innate immune cells in cancer immunotherapy. Sci China Life Sci. 62, 633–639 (2019).Article PubMed CAS Google Scholar Liu, Y. et al. Anti-EGFR chimeric antigen receptor-modified T cells in metastatic pancreatic carcinoma: a phase I clinical trial. Cytotherapy 22, 573–580 (2020).Article PubMed Google Scholar Bagley, S. J. et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nat. Med. 30, 1320–1329 (2024).Article PubMed PubMed Central CAS Google Scholar Jaeger-Ruckstuhl, C. A. et al. Phase I study of ROR1-specific CAR-T cells in advanced hematopoietic and epithelial malignancies. Clin. Cancer Res. 31, 503–514 (2025).Article PubMed PubMed Central CAS Google Scholar Budi, H. S. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor (CAR) for tumor immunotherapy; recent progress. Stem Cell Res. Ther. 13, 40 (2022).Article PubMed PubMed Central CAS Google Scholar Strecker, M. I. et al. AAV-mediated gene transfer of a checkpoint inhibitor in combination with HER2-targeted CAR-NK cells as experimental therapy for glioblastoma. Oncoimmunology 11, 2127508 (2022).Article PubMed PubMed Central CAS Google Scholar Ma, R. et al. An oncolytic virus expressing IL15/IL15Rα combined with off-the-shelf EGFR-CAR NK cells targets glioblastoma. Cancer Res. 81, 3635–3648 (2021).Article PubMed PubMed Central CAS Google Scholar Tao, B. et al. Engineering CAR-NK cell-derived exosome disguised nano-bombs for enhanced HER2-positive breast cancer brain metastasis therapy. J. Control. Release 363, 692–706 (2023).Article PubMed CAS Google Scholar Kara, G., Calin, G. A. & Ozpolat, B. RNAi-based therapeutics and tumor-targeted delivery in cancer. Adv. Drug Deliv. Rev. 182, 114113 (2022).Article PubMed CAS Google Scholar Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004).Article PubMed CAS Google Scholar Landen, C. N. Jr. et al. Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res. 65, 6910–6918 (2005).Article PubMed CAS Google Scholar Kaiser, P. K. et al. RNAi-based treatment for neovascular age-related macular degeneration by Sirna-027. Am. J. Ophthalmol. 150, 33–39.e32 (2010).Article PubMed CAS Google Scholar Aagaard, L. & Rossi, J. J. RNAi therapeutics: principles, prospects and challenges. Adv. Drug Deliv. Rev. 59, 75–86 (2007).Article PubMed PubMed Central CAS Google Scholar Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nat. Biotechnol. 21, 635–637 (2003).Article PubMed CAS Google Scholar Doench, J. G. et al. Rational design of highly active sgRNAs for CRISPR-Cas9-mediated gene inactivation. Nat. Biotechnol. 32, 1262–1267 (2014).Article PubMed PubMed Central CAS Google Scholar Jiang, C., Lin, X. & Zhao, Z. Applications of CRISPR/Cas9 technology in the treatment of lung cancer. Trends Mol. Med. 25, 1039–1049 (2019).Article PubMed CAS Google Scholar Koo, T. et al. Selective disruption of an oncogenic mutant allele by CRISPR/Cas9 induces efficient tumor regression. Nucleic Acids Res. 45, 7897–7908 (2017).Article PubMed PubMed Central CAS Google Scholar Tsai, J. M., Nowak, R. P., Ebert, B. L. & Fischer, E. S. Targeted protein degradation: from mechanisms to clinic. Nat. Rev. Mol. Cell Biol. 25, 740–757 (2024).Article PubMed CAS Google Scholar Alabi, S. B. & Crews, C. M. Major advances in targeted protein degradation: PROTACs, LYTACs, and MADTACs. J. Biol. Chem. 296, 100647 (2021).Article PubMed PubMed Central CAS Google Scholar Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77.e63 (2018).Article PubMed CAS Google Scholar Powell, C. E. et al. Chemically induced degradation of anaplastic lymphoma kinase (ALK). J. Med. Chem. 61, 4249–4255 (2018).Article PubMed PubMed Central CAS Google Scholar Hong, D. et al. Recent advances in the development of EGFR degraders: PROTACs and LYTACs. Eur. J. Med. Chem. 239, 114533 (2022).Article PubMed CAS Google Scholar Wang, H. et al. Discovery of a molecular glue for EGFR degradation. Oncogene 44, 545–556 (2025).Article PubMed Google Scholar Banik, S. M. et al. Lysosome-targeting chimeras for degradation of extracellular proteins. Nature 584, 291–297 (2020).Article PubMed PubMed Central CAS Google Scholar Simonetta, K. R. et al. Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction. Nat. Commun. 10, 1402 (2019).Article PubMed PubMed Central Google Scholar Lew, E. D. et al. Differential TAM receptor-ligand-phospholipid interactions delimit differential TAM bioactivities. eLife 3, e03385 (2014).Article PubMed PubMed Central Google Scholar Kirane, A. et al. Warfarin blocks Gas6-mediated Axl activation required for pancreatic cancer epithelial plasticity and metastasis. Cancer Res. 75, 3699–3705 (2015).Article PubMed PubMed Central CAS Google Scholar Paolino, M. et al. The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 507, 508–512 (2014).Article PubMed PubMed Central CAS Google Scholar Tsou, W. I. et al. Receptor tyrosine kinases, TYRO3, AXL, and MER, demonstrate distinct patterns and complex regulation of ligand-induced activation. J. Biol. Chem. 289, 25750–25763 (2014).Article PubMed PubMed Central CAS Google Scholar Garcia, J. et al. Bevacizumab (Avastin®) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat. Rev. 86, 102017 (2020).Article PubMed CAS Google Scholar Kariolis, M. S. et al. An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat. Chem. Biol. 10, 977–983 (2014).Article PubMed PubMed Central CAS Google Scholar Harding, T. C. et al. Blockade of nonhormonal fibroblast growth factors by FP-1039 inhibits growth of multiple types of cancer. Sci. Transl. Med. 5, 178ra139 (2013).Article Google Scholar Tabernero, J. et al. First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov. 3, 406–417 (2013).Article PubMed CAS Google Scholar Kashima, Y. et al. Single-cell analyses reveal diverse mechanisms of resistance to EGFR tyrosine kinase inhibitors in lung cancer. Cancer Res 81, 4835–4848 (2021).Article PubMed PubMed Central CAS Google Scholar Izumi, M. et al. Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer. Cell Death Dis 15, 580 (2024).Article PubMed PubMed Central CAS Google Scholar Wang, Q. et al. Single-cell profiling guided combinatorial immunotherapy for fast-evolving CDK4/6 inhibitor-resistant HER2-positive breast cancer. Nat. Commun. 10, 3817 (2019).Article PubMed PubMed Central Google Scholar Chen, J. et al. Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients. Ann. Oncol. 33, 434–444 (2022).Article PubMed CAS Google Scholar Krishna, R. et al. Generalized biomolecular modeling and design with RoseTTAFold All-Atom. Science 384, eadl2528 (2024).Article PubMed CAS Google Scholar Abramson, J. et al. Accurate structure prediction of biomolecular interactions with AlphaFold 3. Nature 630, 493–500 (2024).Article PubMed PubMed Central CAS Google Scholar Leman, J. K. et al. Macromolecular modeling and design in Rosetta: recent methods and frameworks. Nat. Methods 17, 665–680 (2020).Article PubMed PubMed Central CAS Google Scholar Sontheimer-Phelps, A., Hassell, B. A. & Ingber, D. E. Modelling cancer in microfluidic human organs-on-chips. Nat. Rev. Cancer 19, 65–81 (2019).Article PubMed CAS Google Scholar Shibuya, M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis 9, 225–230 (2006).Article PubMed CAS Google Scholar Hussain, R. M., Neiweem, A. E., Kansara, V., Harris, A. & Ciulla, T. A. Tie-2/Angiopoietin pathway modulation as a therapeutic strategy for retinal disease. Expert Opin. Investig. Drugs 28, 861–869 (2019).Article PubMed CAS Google Scholar Nicolo, M., Ferro Desideri, L., Vagge, A. & Traverso, C. E. Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert Opin. Investig. Drugs 30, 193–200 (2021).Article PubMed CAS Google Scholar Lopez-Font, I. et al. Decreased circulating ErbB4 ectodomain fragments as a read-out of impaired signaling function in amyotrophic lateral sclerosis. Neurobiol. Dis. 124, 428–438 (2019).Article PubMed CAS Google Scholar Download referencesAcknowledgementsThis work was supported by grants from the National Natural Sciences Foundation of China [grant number 82473937], the Zhejiang Plan for the Special Support for Top-notch Talents in China [grant number 2022R52029] and Fundamental Research Funds for the Central Universities [grant number 2022ZFJH003].Author informationAuthor notesThese authors contributed equally: Kai Wu, Jia Ji, Ting Sun, Dan Lv, Jingying PanAuthors and AffiliationsState Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, ChinaKai Wu, Jia Ji, Ting Sun, Jingying Pan, Miaojin Zhu, Minghai Wang, Lanjuan Li & Hangping YaoJinan Microecological Biomedicine Shandong Laboratory, Jinan, ChinaKai Wu & Hangping YaoWenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, ChinaDan LvZhejiang Key Laboratory of High-level Biosafety and Biomedical Transformation, Hangzhou Medical College, Hangzhou, ChinaMudan WeiCancer Biology Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USAMinghai WangAuthorsKai WuView author publicationsSearch author on:PubMed Google ScholarJia JiView author publicationsSearch author on:PubMed Google ScholarTing SunView author publicationsSearch author on:PubMed Google ScholarDan LvView author publicationsSearch author on:PubMed Google ScholarJingying PanView author publicationsSearch author on:PubMed Google ScholarMudan WeiView author publicationsSearch author on:PubMed Google ScholarMiaojin ZhuView author publicationsSearch author on:PubMed Google ScholarMinghai WangView author publicationsSearch author on:PubMed Google ScholarLanjuan LiView author publicationsSearch author on:PubMed Google ScholarHangping YaoView author publicationsSearch author on:PubMed Google ScholarContributionsH.P.Y., L.J.L. and M.H.W. conceived the central concept of this review and delineated its overall structure. H.P.Y., K.W., J.J., T.S., D.L. and J.Y.P. contributed to the literature search and wrote the original version of the manuscript. D.L., J.Y.P. and K.W. created the figures. M.D.W. and M.J.Z. participated in reference collection and table organization. H.P.Y., L.J.L. and M.H.W. provided guidance and supervision during the writing process and critically reviewed the manuscript. All authors have read and approved the article.Corresponding authorsCorrespondence to Minghai Wang, Lanjuan Li or Hangping Yao.Ethics declarationsCompeting interestsThe authors declare no competing interests.Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Rights and permissionsOpen Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.Reprints and permissionsAbout this article