IntroductionPersonalized cancer vaccines harnessing patient-specific tumor neoantigens to orchestrate precise antitumor immune responses represent an important advancement in oncology.1 Emerging from conceptual grounds, the field of cancer vaccinology has progressed through three technological revolutions: early peptide-based formulations, dendritic cell (DC) vaccines primed with tumor lysates, and contemporary platforms integrating next-generation sequencing (NGS) with artificial intelligence (AI)-driven neoantigen prediction.2 The evolutionary trajectory of these vaccines is marked by pivotal milestones across distinct developmental phases (Fig. 1). The foundational era (1970–2010) established critical immunological principles, beginning with the demonstration of the first clinically effective autologous tumor-cell vaccine for melanoma by Laucius et al. in 1977,3 followed by the discovery and isolation of the first T-cell-recognized neoantigen P91A in a mouse tumor model by De Plaen et al. in 1988.4 Subsequent breakthroughs included a modified autologous melanoma vaccine developed by Sato et al. in 19975 and U.S. Food and Drug Administration (FDA) approval of the first personalized DC vaccine developed by Kantoff et al. in 2010.6 The technological maturation phase (2011–2020) witnessed paradigm-shifting innovations catalyzed by the application of whole-exome sequencing for systematic neoantigen identification by Robbins et al. in 2013.7 This era witnessed the demonstration of enhanced T-cell repertoire diversity through the use of neoantigen-pulsed DCs in patients with melanoma by Carreno et al.,8 while Ott et al.9 and Sahin et al.10 translated preclinical concepts into clinical reality through pioneering trials of personalized peptide-based and RNA-based poly-neoepitope vaccines in patients with melanoma. As of 2020, clinical validation accelerated, with landmark studies including Rojas et al., who combined the BNT122 RNA vaccine with checkpoint inhibition in pancreatic cancer,11 and Weber et al.,12 who demonstrated the superior efficacy of an mRNA-4157/pembrolizumab regimen in melanoma. Recent advances, including the characterization of durable CD8+ T-cell memory post-vaccination,13 underscore the field’s transition to robust therapeutic platforms. In the era of precision medicine and AI-driven medicine, future directions converge on AI-optimized personalized cancer vaccine design, as exemplified by the Stargate Project aiming to accelerate the development of AI-driven mRNA vaccines14,15 and novel biomimetic approaches, such as cancer cell membrane-based vaccines,16,17 positioning personalized immunotherapy at the vanguard of precision oncology.Fig. 1Full size imageImportant events in the development of personalized cancer vaccine research. DC dendritic cell, FDA Food and Drug Administration (Created with Adobe Photoshop)Personalized cancer vaccines are a form of immunotherapy wherein a patient’s specific resected or biopsied tumor tissue serves as the antigen source, representing their unique tumor mutanome and actual immune state; these neoantigens are then formulated with immune-stimulating adjuvants and delivered via various platforms (e.g., mRNA, peptides, or dendritic cells) to elicit a targeted antitumor response.1 This personalized immunization strategy stands in contrast to adoptive cell therapies (ACTs), such as tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)-T and chimeric antigen receptor (CAR)-T cells, which function as ex vivo-manufactured “living drugs.”18,19 ACTs involve isolating or engineering T cells for direct reinfusion, enabling an immediate, powerful cytotoxic attack, albeit often focused on single or limited antigens and frequently hampered by severe toxicity, complex logistics, and antigen escape.20 Conversely, the personalized cancer vaccine approach aims to orchestrate a de novo, polyclonal immune response within the host, priming a broader T-cell repertoire against multiple tumor epitopes. While the clinical effect may manifest more gradually than with ACTs, this broad activation offers a potent defense against tumor heterogeneity and, critically, fosters the establishment of durable immunological memory, potentially translating to superior long-term control and prevention of recurrence in solid malignancies.21The current landscape of personalized cancer vaccines reflects both remarkable progress and persistent translational challenges. As of 2019, more than 799 therapeutic cancer vaccines have been documented in the global drug development pipeline, with more than 400 active clinical trials, of which at least 23 employ personalized vaccination strategies for individually tailored therapies.21,22 While early-phase trials have demonstrated sporadic induction of tumor-specific T-cell responses, the field confronts critical barriers to clinical translation, as evidenced by the limited number of advanced-phase trials achieving durable therapeutic endpoints.23 Contemporary tumor immunotherapies face four interrelated biological challenges: (1) dynamic antigenic heterogeneity, arising from clonal evolution and immunoediting, which progresses faster than therapeutic vaccine development cycles, (2) immunosuppressive tumor microenvironments (TMEs) that exacerbate T-cell exhaustion through dominant programmed death 1 (PD-1)/cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling coupled with nutrient-depleting metabolic reprogramming, (3) discordant interplay between innate immune activation and adaptive effector functions, manifesting particularly in impaired DC-T-cell communication networks, and (4) therapeutically induced immunological memory that remains ineffective against tumor recurrence.2,21 These biological hurdles are exacerbated by manufacturing constraints; current neoantigen peptide/mRNA platforms require 12–16 weeks for design, validation, and good manufacturing practice-compliant production, a timeframe incompatible with the clinical trajectories of rapidly progressive cancers.23 Furthermore, the lack of standardized criteria for neoantigen prioritization (e.g., major histocompatibility complex [MHC]-binding affinity vs. tumor clonality) and scalable vector systems for multiepitope delivery hinders reproducible vaccine efficacy across heterogeneous patient populations.24 Addressing these limitations requires (1) sequencing technology advancements, such as real-time tumor sequencing, to identify the potential vaccine-responsive population and machine learning or AI-guided antigen selection to compress development timelines while maintaining therapeutic specificity, and (2) novel delivery systems, including novel biomaterial delivery platforms to overcome antigen tolerance and the suppressive TME and increase targeting accumulation in lymphoid tissues.Nanotechnology has changed cancer vaccinology by enabling precision engineering of immune-modulatory systems that address fundamental limitations in conventional vaccine design.25 The developmental trajectory of nanovaccines has progressed through three evolutionary phases: (1) first-generation lipid nanoparticles (LNPs) focused on stabilizing antigens and enhancing DC uptake, exemplified by the COVID-19 mRNA vaccine platform,26 (2) second-generation stimuli-responsive carriers incorporating TME-sensitive materials, such as hypoxia-cleavable linkers or pH-triggered polymers for spatiotemporally controlled drug release,27 and (3) current third-generation “smart” systems integrating targeting ligand modification, bioinspired materials, and nanomaterial-guided antigen-adjuvant codelivery.28 These engineered nanostructures leverage size-dependent biodistribution (20–200 nm optimal for lymphatic trafficking) and surface charge modulation (–10 to +20 mV zeta potential for prolonged circulation half-life). Advanced platforms employ multicompartment architectures to coencapsulate neoantigens with stimulators of interferon genes (STING)/Toll-like receptor (TLR)9 agonists within pH-sensitive poly(lactic-co-glycolic acid) matrices, achieving high lymph node accumulation efficiency compared to that of conventional emulsion-based adjuvants.29 Such orchestrated delivery enables synchronized antigen cross-presentation via MHC-I/MHC-II pathways and danger signal activation, generating polyfunctional CD8+/CD4+ T-cell responses with greater tumor cytotoxicity than peptide/adjuvant cocktails.30 Recent innovations include DNA origami nanostructures that enable programmable spatial epitope patterning to mimic viral surface topology, which enhances B-cell receptor clustering and germinal center reactions in preclinical models.31 Therefore, vaccine design enabled by advanced materials may change the field of therapeutic cancer vaccines.Nanotechnology combined with personalized cancer vaccine design may provide potent and safe cancer vaccines by overcoming the limitations of conventional neoantigen-centric approaches.32,33 For instance, cancer cell membrane-coated nanoplatforms uniquely preserve complete tumor antigen profiles, including native post-translational modifications and spatial epitope arrangements that are typically destroyed during synthetic peptide manufacturing, thereby allowing dynamic adaptation to the tumor’s evolving mutational landscape.34 This strategy fundamentally addresses antigenic obsolescence by incorporating whole-tumor lysates containing dynamically updated antigen repertoires to counter tumor evolution. Advanced bioresponsive carriers further enhance therapeutic precision through controlled antigen release mechanisms triggered by T-cell activators, such as IFN-γ, establishing adaptive immune modulation synchronized with real-time host responses.35,36 These systems also pioneer predictive vaccine optimization through systematic integration of multiomics data, correlating patient-specific immune parameters (e.g., T-cell receptor [TCR] clonality patterns, myeloid suppressor cell infiltration) with material design characteristics (e.g., ligand spatial distribution, degradation profiles).37 Nanomaterial innovation combined with systems immunology enables iterative vaccine design that adapts to both tumor evolution and individual immune contexts, establishing a novel framework for precision oncology in which engineered therapeutics dynamically interface with biological complexity.While prior reviews have extensively discussed advancements in neoantigen prediction algorithms, clinical trial outcomes, and specific delivery platforms (e.g., mRNA vaccines), they often underrepresent the integrated chains of personalized cancer vaccines, including antigens, adjuvants, delivery platforms, clinical trials, and regulatory.1,21,23,38 The literature predominantly addresses immunological mechanisms or technological workflows in isolation, leaving a critical gap in understanding how nanomaterial innovations, such as hybrid lipid-polymer architectures, stimuli-responsive carriers, and biomimetic membrane systems, synergize with immunological principles to overcome translational barriers.39,40,41 In addition, some emerging studies have also focused on the structure‒function relationships and therapeutic mechanisms of nanomedicines, expanding the new insights into the design of next-generation nanomedicines against diseases.42,43,44 Compared with previous reviews, this work provides a comprehensive and up-to-date review of personalized cancer vaccines, positioning them at the intersection and broader scope of cancer immunology, precision medicine, and advanced biotechnology. Moving beyond a narrow technological focus, we first explore the fundamental rationale and classifications of personalized vaccines, including mRNA, DNA, peptide, dendritic cell, and whole-cell platforms, situating them within the broader cancer-immunity cycle. We then systematically address the major immunological and logistical barriers that have limited vaccine efficacy, such as tumor heterogeneity, immunosuppressive microenvironments, and inadequate immune memory formation. The role of nanotechnology is carefully examined as one key enabler among several, highlighting how rational material design can enhance antigen presentation, support codelivery of adjuvants, and promote sustained immune activation without overshadowing other critical platforms and strategies. In addition, we survey the expanding clinical applications of personalized vaccines across cancer types, both as monotherapies and in combination with immunomodulators, chemotherapy, radiotherapy, or cell-based therapies, with particular emphasis on their potential in preventing recurrence and metastasis. Finally, the review discusses pathways toward clinical translation and commercialization, addressing challenges related to manufacturing, regulation, and cost-effectiveness, while also considering emerging tools such as AI-based antigen selection and novel delivery platforms. By integrating diverse perspectives, including immunological, biomedical, engineering, and regulatory perspectives, this work aims to offer a balanced and forward-looking resource for researchers and clinicians alike, facilitating the development of truly effective and accessible personalized cancer vaccines.Classification and basic principles of personalized cancer vaccinesRationale of personalized cancer vaccinesEffective cancer vaccines mediate their antitumour effects by expanding populations of antigen-specific T cells. Upon presentation of tumor antigens by activated antigen-presenting cells (APCs), cognate T cells undergo clonal expansion, often by several orders of magnitude, and traffic to tumor sites to eliminate malignant cells expressing the target epitope. The human T-cell repertoire, comprising trillions of distinct lymphocytes, is capable of discriminating between antigens, short peptides as minimal as eight amino acids—that may differ by only a single residue. This exquisite specificity enables T cells to recognize mutant epitopes such as those derived from the KRASG12D oncoprotein, which differs from wild-type KRAS by a single amino acid substitution.45 Cancer vaccines are typically designed to deliver tumor antigens to dendritic cells, the most potent APCs, to initiate robust T-cell activation. Once primed, antigen-specific T cells expand, circulate, and systemically infiltrate tumors to execute cytotoxic functions.46,47Cancer personalized medicine entails therapeutic strategies precisely tailored to the distinct genetic and molecular profile of an individual patient’s tumor, thereby targeting its unique pathogenic features.48,49,50 Two principal categories of tumor antigens are recognized: tumor-specific antigens (TSAs), which encompass viral oncoproteins and neoantigens derived from nonsynonymous somatic mutations,51 and tumor-associated antigens (TAAs), which include tissue-lineage-specific and developmental-stage-specific antigens.52 Within this framework, we further distinguish two classes of personalized tumor antigens: predefined personalized antigens, referring typically to predetermined neoantigens identified from patient genomic data, and anonymous personalized antigens, which comprise the full spectrum of tumor antigens elicited and characterized ex vivo from individual patients (Fig. 2).53,54,55Fig. 2Full size imageClassifications of personalized tumor antigens and the mechanism of action of personalized cancer vaccines. The multifaceted process of personalized antigen presentation and T-cell activation in antitumor immunity begins with the acquisition of tumor samples via biopsy or surgery, which are then utilized for either in silico neoantigen prediction or ex vivo personalized antigen (such as cancer cells, cancer cell lysates, or cancer cell membranes) anonymous loading. Antigens are processed and presented by APCs, including migratory and lymph node-resident DCs, via MHC class I and II molecules, leading to the priming and activation of CD4⁺ and CD8⁺ T cells. Activated effector T cells traffic to the tumor site, where they mediate the killing of tumor cells, while memory T cells and cross-reactive responses contribute to sustained immune surveillance (Created with Adobe Photoshop)Predefined personalized antigensIn contrast to shared antigens prevalent across patient cohorts, predefined personalized antigens are unique to individual patients and most frequently correspond to neoepitopes derived from TSAs (Fig. 2). Targeting these patient-specific neoepitopes enables exquisite precision in immune recognition, engaging T-cell clones that have escaped thymic negative selection. When combined with immune checkpoint blockade, such targeting can provoke broad and potent T-cell responses in vaccinated individuals.10,56 Advances in next-generation sequencing, along with the integration of complementary immunostimulatory components, such as DC recruitment and activation, modulation of myeloid suppression, and provision of CD4⁺ T-cell help, have significantly enhanced the feasibility and efficacy of personalized cancer vaccines.23 The development process typically involves DNA and RNA extraction from paired tumor and germline samples for exome and transcriptome sequencing, coupled with high-resolution HLA typing57 (Fig. 2). Somatic mutations are rigorously filtered to include only those present exclusively in the tumor, characterized by a low false discovery rate and resulting in nonsynonymous amino acid changes. Putatively immunogenic neoepitopes are subsequently predicted in silico based on their binding affinity to the patient’s HLA alleles using tools such as NetMHC.58 Candidates are further prioritized according to tumor RNA expression levels, culminating in the selection of up to 20 neoepitopes for vaccine construction. These are synthesized as good manufacturing practice (GMP)-grade peptides, RNA constructs, or viral vectors. Formulations often include adjuvants such as liposomes to enhance antigen uptake by APCs or pattern-recognition receptor agonists to promote APC activation and strengthen immunogenicity.59 Although the process remains resource-intensive and complex, improvements in sequencing throughput and the incorporation of machine learning into epitope prediction are steadily enhancing its scalability and predictive accuracy.60,61,62 Recent evidence indicated that in patients responsive to vaccination, personalized multiepitope vaccines, designed according to the aforementioned prediction pipeline, induced CD8⁺ T-cell clones with an estimated average lifespan of 7.7 years, ranging from 1.5 to nearly 100 years. Notably, approximately 20% of these clones exhibit latent, multidecade persistence, potentially extending beyond the lifetime of the host. Furthermore, 86% of the vaccine-induced T-cell clones per patient remained detectable at substantial frequencies nearly three years post-vaccination, including populations characterized by high avidity for tumor neoepitopes.13Nevertheless, the identification of optimal neoantigens capable of eliciting robust antitumour responses remains a formidable challenge.63,64 Tumor heterogeneity represents a major hurdle: subclonal antigen expression may enable immune escape, wherein cancer cells lacking the targeted epitope continue to proliferate. To mitigate this, multiepitope vaccines targeting dozens of neoantigens are increasingly explored.65,66 The selection of ideal vaccine antigens is governed by numerous variables, including peptide–HLA-binding affinity and T-cell receptor (TCR) recognition kinetics. Although biophysical principles suggest that these interactions should be predictable, the extreme diversity of HLA and TCR repertoires complicates universal prediction.67 Efforts are underway to leverage deep learning data and results from preclinical and clinical studies to train machine learning models for improved patient-specific antigen selection.68,69,70 However, the utility of such approaches is constrained by practical limitations, such as incomplete sampling of tumor regions and the T-cell repertoire, which may miss relevant antigens in metastases or fail to account for the full spectrum of TCR specificities. For instance, in a phase I trial of the autogene cevumeran mRNA vaccine, which utilized computational prioritization of neoantigens from resected pancreatic tumors, only 25 out of 230 predicted neoepitopes (11%) across 16 patients induced detectable T-cell responses, underscoring the persistent gap between prediction and immunogenicity.11 In addition, the time-consuming nature of neoantigen prediction remains another significant bottleneck (average 2–4 months), primarily due to the complex multistep computational pipelines involving somatic variant calling, HLA typing, epitope binding affinity prediction, and RNA expression validation.23 This process often requires extensive bioinformatic scrutiny and experimental verification, which can delay the timely development of personalized vaccines and adoptive T-cell therapies, particularly for cancers with high mutational burden or heterogeneity. Ongoing efforts to optimize algorithms and integrate machine learning aim to accelerate prediction, yet achieving both speed and accuracy continues to pose a considerable translational challenge.24 Moreover, the concept of the therapeutic window in chimeric antigen receptor T-cell therapy may be referenced to develop a similar management protocol for neoantigen vaccination.71Anonymous personalized antigens ex vivoGiven the persistent challenges in defining optimal antigens, an alternative vaccination strategy has emerged that bypasses the need for precise antigen identification. Instead, this approach leverages the innate capacity of the immune system to select immunogenic targets by facilitating the colocalization of whole-tumor cells or their derivatives with APCs.72 Therefore, even when effective, the specific antigens eliciting responses may remain unknown or anonymous. Unlike predefined antigen vaccines, anonymous antigen platforms can incorporate novel antigen classes such as peptide fusion epitopes and posttranscriptionally modified variants, which are technically challenging to identify and thus absent from most neoantigen pipelines.73,74 Ex vivo methods typically involve surgical resection of tumor tissue, processing into an immunogenic format, and loading onto APCs before reinfusion. Alternatively, whole-tumor cell or lysates and tumor-cell membrane strategies rely on endogenous mechanisms of antigen capture and presentation by tissue-resident DCs.75 Both modalities share the fundamental principle of leveraging uninstructed, polyclonal immune recognition, potentially enabling responses against a more diverse and therapeutically relevant antigenic landscape than is possible with current targeted approaches. A key advantage of such approaches is their capacity to present a broader repertoire of antigens, including oncogenic fusion proteins, splice variants, endogenous retroelements, and posttranslationally modified proteins, than currently achievable through computational neoantigen prediction.76 These antigen categories are often excluded from conventional personalized vaccines due to technical limitations in identification and prediction. The critical factor for success is the efficient uptake and processing of tumor material by professional APCs, particularly conventional dendritic cells type 1 (cDC1), coupled with antigen processing and cross-presentation.77 This can be achieved through three primary strategies: autologous whole-tumor cells or lysates, ex vivo loading, where autologous APCs are cocultured with processed tumor cells or lysates, and autologous tumor-cell membrane (Fig. 2).Tumor cells or their lysates encompass not only canonical neoepitopes arising from nonsynonymous mutations but also a diverse array of noncanonical antigens, including splice variants, posttranslationally modified proteins, endogenous retroviral elements, and overexpressed shared TAAs.78 This broad antigenic repertoire closely mirrors the individual tumor’s molecular landscape, capturing subclonal variants and spatially heterogeneous antigens often overlooked by targeted sequencing approaches [35481358]. By preserving native antigen conformation and contextual signals such as chaperone complexes and damage-associated molecular patterns (DAMPs), whole-tumor cells and lysates provide a physiologically relevant stimulus that enhances cross-presentation by dendritic cells and promotes robust T-cell activation.79 Clinical evidence indicated that all 10 evaluated patients displayed a robust vaccine-induced response, indicated by increased frequencies of Ki67+ and activated PD-1+ circulating T cells in a phase 1 trial of autologous DCs pulsed with allogeneic tumor-cell lysate.80 Nevertheless, this approach is not without limitations. The use of unfractionated material introduces the risk of inducing tolerance to self-antigens or amplifying immune responses against nonmalignant tissues, potentially leading to autoimmunity.81 Furthermore, the variable composition and quality of tumor samples, affected by necrotic content, stromal contamination, and low tumor cellularity, may result in inconsistent antigen presentation and reduced immunogenicity. Additionally, the very breadth of antigens presented complicates the monitoring and mechanistic understanding of effective immune responses, as the specific antigens driving tumor regression remain largely undefined.82Ex vivo antigen loading entails the isolation of patient-derived APCs, most commonly monocyte-derived dendritic cells, which are subsequently pulsed in vitro with tumor-derived materials such as irradiated whole cells, lysates, or purified membrane fractions.83 This process enables the presentation of a diverse repertoire of tumor antigens, including both defined and uncharacterized epitopes, while offering the opportunity to enhance APC immunogenicity through cytokine activation (e.g., GM-CSF, IL-4, or type I interferons) or exposure to molecular adjuvants such as Toll-like receptor agonists.84 Following antigen uptake and processing, the loaded APCs are reinfused into the patient, where they traffic to secondary lymphoid organs and engage naïve T cells, thereby initiating a broad polyclonal antitumor response capable of targeting epitopes that are often neglected by computational prediction algorithms.85 Despite its broad-antigen coverage and physiological relevance, this strategy faces several translational challenges. The requirement for specialized cell-processing facilities adhering to GMP standards renders the process logistically complex, costly, and time-consuming. Furthermore, the variability in the quality and composition of starting material, such as tumor cellularity, viability, and the extent of necrosis, can lead to inconsistencies in antigen presentation and T-cell priming efficacy.86 There is also the risk that repeated ex vivo manipulation may alter the functional properties of APCs, impairing their migratory capacity or survival upon reinfusion. Additionally, since antigenic targets remain largely undefined, immune monitoring and response validation become considerably more challenging than vaccines targeting predefined neoantigens.87,88The incorporation of tumor-cell membrane components or engineered membrane vesicles (such as cancer-derived exosomes) as antigen sources constitutes an emerging refinement in personalized cancer vaccine design.89,90 These membrane-based platforms preserve the native surface proteome and spatial architecture of tumor antigens, including multiepitope complexes, posttranslationally modified proteins, and densely clustered antigen arrays, which are critical for eliciting high-avidity T-cell responses and enhancing immune recognition.91 The nature of the cell membrane renders it an applicable candidate for nanovaccines.92 Tumor-cell membrane antigens are very abundant, reducing the impact of excessive cytoplasmic antigens on the immune tolerance of DCs.93 In addition, tumor-cell membrane-based vaccines reduce the risk of nucleic acid insertion in tumor cells.16 However, several challenges remain to be addressed. The isolation and purification of tumor membranes require sophisticated technical protocols to maintain structural integrity and antigenicity, often resulting in variable batch quality and scalability issues. Furthermore, the inclusion of normal cell membrane components in tumor tissues raises the potential for autoimmunity, necessitating careful purification to enrich for tumor-specific motifs. Another limitation lies in the inefficient cross-presentation of membrane-derived antigens by DCs, which may require additional engineering, such as fusion with immunostimulatory molecules or codelivery with potent adjuvants to enhance immunogenicity.17Core immunological principles of personalized cancer vaccinesPersonalized tumor antigen-specific T-cell immunity operates through fundamental mechanisms of the cancer-immunity cycle, processes that occur across two principal anatomical domains: the TME and LNs.94 Like any endogenously expressed cellular protein, personalized tumor antigens expressed by cancer cells undergo proteasomal degradation into short peptides. These peptides are subsequently processed within the endoplasmic reticulum and loaded onto MHC-I molecules. The resulting peptide-MHC-I complexes, including those presenting neoantigens, are then displayed on the surface of tumor cells for recognition by CD8+ T cells. Priming of naïve T cells occurs almost exclusively within LNs, mediated by highly specialized resident DCs. These APCs acquire soluble personalized tumor antigens either directly from drained lymphoid vessels or indirectly via transfer from migratory DCs that have internalized antigens in the periphery. DCs are further capable of cross-presentation, a process by which endocytosed antigens are channeled into the cytosol for proteasomal degradation and subsequent loading onto MHC-I molecules, thereby initiating and stimulating CD8+ T-cell responses. Upon encountering antigens under appropriate costimulatory conditions, naïve CD8+ and CD4+ T cells become activated, undergo clonal expansion through iterative rounds of cell division, and exit LNs as effector and memory T cells. These activated T cells then traffic to and infiltrate the tumor site. Within an immunosuppressive TME, personalized tumor antigen-specific T cells exert their effector functions by recognizing antigens presented both by intratumoral APCs and directly on tumor cells, mediating indirect or direct tumor control. The ultimate goal of cancer vaccination is to reignite the cancer-immunity cycle, either by priming new neoantigen-specific T-cell responses or by activating preexisting ones, thereby fostering a sustained adaptive immune response capable of mediating complete tumor eradication.64Classifications of personalized cancer vaccinesPersonalized cancer vaccines can be categorized into several types based on their formulation platforms and mechanisms of action, including personalized DNA vaccines, personalized mRNA vaccines, personalized peptide vaccines, personalized DC vaccines, and personalized tumor-cell-based vaccines. These vaccines share the common goal of targeting patient-specific tumor antigens (particularly neoantigens) to activate a robust immune response, thereby enabling precise attacks on tumors (Fig. 3).Fig. 3Full size imageClassification of personalized cancer vaccines. There are many strategies for developing personalized cancer vaccines derived from patient tumor samples obtained via surgery or biopsy. Tumor tissues are used to generate DNA, mRNA, peptide vaccines, or ex vivo-loaded DC vaccines, which are then administered back to the patient. Alternatively, whole-tumor cells or tumor-cell membranes can be processed and presented by DCs. These DCs uptake, process, and present personalized tumor antigens, leading to T-cell priming and activation within the lymph node. Subsequently, activated T cells infiltrate the tumor site, resulting in cancer cell death. Key intracellular processes such as endocytosis, translation, endosome escape, and antigen release are involved in antigen presentation, aided by cytokine stimulation (Created with Adobe Photoshop)Personalized DNA cancer vaccinesDNA-mediated immunization emerged in the 1990s with the demonstration that a plasmid encoding influenza A nucleoprotein could induce a protective and specific cytotoxic T-lymphocyte (CTL) response.95 Advances in whole-genome sequencing and DNA microarrays have since enabled the comprehensive identification of TSAs, facilitating the development of personalized cancer treatments. In this context, DNA vaccination represents a promising immunotherapeutic strategy by delivering antigen-encoding plasmids that elicit or enhance adaptive immune responses against tumor cells.96 These vaccines are typically composed of plasmid DNA molecules engineered to express TAAs or TSAs under the control of a mammalian promoter.97 Upon administration, commonly via intradermal or intramuscular routes, the plasmid is taken up by host cells, including myocytes, keratinocytes, and resident APCs.98 Following transfection and nuclear entry, the antigen is expressed and processed, leading to the presentation of immunogenic epitopes on MHC molecules. This ultimately activates CD4⁺ and CD8⁺ T cells, initiating both cellular and humoral immune responses. When APCs are directly transfected, endogenous antigens are primarily presented via MHC-I to CD8⁺ T cells, although cross-presentation via MHC-II to CD4⁺ T cells also occurs, contributing to humoral immunity (Fig. 3).99,100 Although nonprofessional cells such as myocytes can express antigens effectively, professional APCs are essential for robust antigen presentation and immune activation [40449971]. DNA vaccines also stimulate innate immunity through cytosolic DNA-sensing pathways, triggered by features such as CpG motifs and double-stranded DNA structure, thereby acting as intrinsic “danger signals”.101Early cancer DNA vaccines primarily targeted nonmutated TAAs, but these often suffer from immune tolerance due to their expression in normal tissues, limiting their efficacy and contributing to mixed outcomes in clinical trials.102 In contrast, personalized neoantigens arise from tumor-specific genetic alterations and encode novel epitopes not found in healthy tissues. Their cancer-restricted expression minimizes off-target effects and circumvents central tolerance, making them attractive targets for therapeutic vaccination.103 Moreover, personalized neoantigens can enhance immunogenicity within the tumor microenvironment, promoting the transition from immunologically “cold” to “hot” tumors, and may upregulate PD-L1 expression, thereby potentially expanding the efficacy of anti-PD-1/PD-L1 immunotherapy.104 Personalized neoantigens are presented by antigen-presenting cells to both CD4⁺ and CD8⁺ T cells, initiating a specific antitumor response that is not constrained by self-tolerance mechanisms.59 The identification of neoantigens typically begins with exome sequencing of tumor biopsies, followed by comparison with matched normal tissue to pinpoint somatic mutations. Computational algorithms then predict which mutations yield peptides with high affinity for MHC class I or II molecules. Candidate epitopes are subsequently validated through in vitro and in vivo assays to confirm their ability to stimulate T-cell responses, particularly from CD8⁺ and CD4⁺ T cells.105 Nevertheless, not all predicted peptides are immunogenic, and accurately prioritizing immunogenic mutations remains a major challenge. Notably, DNA vaccines appear to elicit stronger CD8⁺ T-cell responses against neoantigens than RNA- or peptide-based platforms, highlighting their potential for enhanced efficacy in cancer vaccination.106 Once identified and validated, personalized neoantigens can be cloned and inserted into DNA vaccine vectors, enabling the development of highly individualized immunotherapies tailored to the unique mutational landscape of each patient’s tumor. Neoantigen DNA vaccines have been reported to induce neoantigen-specific T-cell responses and overall survival in patients with various cancers.106,107 Currently, various nanoparticle-coated personalized DNA vaccines, such as various LNP formulations for delivering DNA-encoded biologics, induce stronger T-cell immune responses and antigen-specific antibodies than electroporation.108,109,110,111 Compared to peptide-based vaccines, DNA vaccines offer several advantages: they can encode full-length antigens targeting multiple epitopes, incorporate immune-modulatory elements to enhance responses, and are associated with relatively straightforward production and favorable safety profiles. Relative to mRNA vaccines, DNA constructs exhibit greater membrane diffusion compatibility with lipid-based delivery systems112 and possess longer half-lives, enabling sustained antigen expression.113 However, DNA vaccines carry risks of insertional mutagenesis and require cell-based production, which introduces concerns about microbial contamination, a significant consideration in immunocompromised patients.114Personalized mRNA cancer vaccinesMessenger RNA (mRNA) is a single-stranded macromolecule that carries genetic information from nuclear DNA to the ribosome, where it is translated into functional proteins in the cytoplasm.38 This molecular basis underpins the application of mRNA in cancer vaccines, whereby designed transcripts encoding TAAs or TSAs are delivered into the cytoplasm of host cells, typically APCs, leading to the expression of target antigens.115 These antigens are subsequently presented on the surface of APCs via MHCs, thereby initiating potent antitumour immune responses. mRNA vaccines elicit both humoral immunity, mediated by antibodies and B cells, and cellular responses involving CD4+ T helper and CD8+ cytotoxic T cells, which collectively contribute to the efficient elimination of malignant cells.116 Furthermore, mRNA is nonintegrating and noninfectious, conferring a favorable safety profile with minimal genomic risk.117 Following cellular internalization and cytosolic delivery, the mRNA is translated by ribosomes into proteins that undergo post-translational modifications to form correctly folded, functional antigens (Fig. 3). Any residual in vitro transcribed (IVT) mRNA is degraded through natural physiological processes, mitigating potential metabolite toxicity.118Inspired by recent phase I/II clinical trials, personalized mRNA vaccines encoding neoantigens (such as the autogenes cevumeran and mRNA-4157) have been demonstrated to be well tolerated and capable of inducing robust immune responses with high efficiency in patients with advanced cancers119,120 (Table 1). The use of IVT enables template-directed synthesis of RNA sequences ranging from short oligonucleotides to several kilobases in length, facilitating cell-free production that avoids microbial contamination and quality control issues associated with cell-based systems.121 This approach not only enhances manufacturing efficiency but also simplifies downstream purification, enabling rapid, scalable, and cost-effective production. Advances in in vivo delivery systems have further improved mRNA vaccine efficacy through formulation into carrier nanoparticles, promoting efficient cellular uptake and cytosolic expression.122,123 In addition to conventional nonreplicating mRNA, self-amplifying mRNA (SAM) or replicon RNA (repRNA), derived from alphavirus genomes, retains the viral RNA replication machinery while replacing structural genes with antigen-encoding transgenes.124 This design promotes robust RNA amplification within host cells, significantly enhancing antigen expression and immune activation.125 The emergence of precision medicine, which tailors healthcare interventions to individual genetic profiles, has provided genomic insights into disease susceptibility and transformed strategies for disease prevention and treatment. By incorporating patient-specific TSAs, mRNA-based cancer vaccines can be personalized to maximize therapeutic efficacy and safety, ushering in a new era of individualized oncologic care.126 Despite these advantages, mRNA vaccine development faces several challenges. Unmodified mRNA is inherently unstable and susceptible to rapid degradation by extracellular RNases, impairing efficient uptake by APCs. Moreover, mRNA possesses intrinsic immunostimulatory properties that can activate interferon-mediated innate immune pathways. While this self-adjuvant effect may enhance immune activation, it can also accelerate mRNA degradation and suppress antigen expression. Additionally, impurities such as double-stranded RNA (dsRNA) generated during IVT may exacerbate innate immune activation and further impede translational efficiency.127,128,129,130Table 1 Completed clinical trials of personalized cancer vaccines with published results (via clinicaltrial.gov)Full size tablePersonalized peptide cancer vaccinesSince the pioneering work by Hu et al. demonstrating the clinical potential of a MAGE-1-derived peptide as a cancer vaccine, numerous tumor antigen-derived epitopes have been explored for peptide-based vaccination strategies.131 In recent years, TAAs have been extensively explored in cancer vaccine development. These include differentiation antigens (e.g., tyrosinase, gp100, and MART-1), cancer-testis antigens (such as MAGE-A family members, NY-ESO-1, and PRAME), and overexpressed self-antigens. While such peptides are shared among patients and provide broad applicability, their expression in normal tissues imposes constraints due to self-tolerance mechanisms, often resulting in diminished immune activation or potential autoimmunity.132,133 Consequently, TAA-based peptide vaccines must achieve a balance between immunogenicity and safety.134 More recently, research has shifted toward personalized TSAs, or neoantigens, which arise from tumor-specific alterations, including missense mutations, insertions and deletions, frameshift mutations, activation of endogenous retroelements, or post-translational modifications such as phosphorylation, glycosylation, and methylation.135 Such peptides evade central tolerance and are capable of eliciting potent and specific T-cell responses. However, neoantigens are often patient-specific, whose identification remains costly and labor-intensive, and they are susceptible to immune editing and escape mechanisms, leading to dynamic changes in antigenicity.136 Thus, effective neoantigen-directed peptide vaccines generally incorporate multiple antigenic peptides to counter tumor heterogeneity and evolutionary adaptation.57 Another critical determinant of immunogenicity is peptide length. Short peptides (8–11 amino acids), representing minimal CD8+ T-cell epitopes, are designed to bind directly to MHC class I molecules.137,138 These peptides are advantageous due to their straightforward synthesis and cost-effective production under clinical-grade conditions. However, their use is constrained by several limitations: short peptides are prone to rapid proteolytic degradation by exopeptidases, reducing their in vivo stability; they exhibit strict HLA restriction, necessitating precise HLA matching between vaccine and patient; and perhaps most importantly, they can bind MHC molecules on nonprofessional APCs, such as lymphocytes, which lack adequate costimulatory signals. This may result in aberrant antigen presentation under noninflammatory conditions, potentially leading to T-cell anergy or tolerance.139,140,141 In contrast, synthetic long peptides (SLPs), typically ranging from 11 to 30 amino acids, require internalization and processing by professional APCs before antigen presentation [20422411, 18438666]. This endogenous processing pathway enables epitopes to be loaded onto both MHC class I and class II molecules, thereby stimulating robust CD8+ cytotoxic T-cell responses as well as CD4+ T helper cell activation.142 The engagement of CD4+ T cells is essential for sustaining effective antitumor immunity through the secretion of cytokines such as IFN-γ, TNF-α, and IL-2, which support CTL function and memory formation. Furthermore, the extended length of SLPs provides opportunities to incorporate additional immune-enhancing motifs, improving both epitope binding and immunogenicity. Ultimately, through professional APC presentation, SLPs promote a more coordinated and durable adaptive immune response, which is critical for mediating tumor-cell elimination (Fig. 3).143,144The identification of applicable peptide epitopes represents a pivotal challenge in the development of personalized cancer vaccines.145 DC-mediated T-cell activation is driven by specific peptide epitopes, rather than full-length antigens, which must exhibit both immunogenicity and compatibility with patient-specific HLA alleles [37768503]. These epitopes are typically short amino acid sequences derived from tumor antigens. Several strategies have been developed to screen for immunodominant epitopes, including bioinformatic predictions and HLA ligandome analyses.146,147 The affinity between HLA-I alleles and candidate peptides can be assessed through various computational methods, such as structural analysis (which calculates binding free energy), position-specific scoring matrices (PSSM), artificial neural networks (ANN), and machine learning-based algorithms. Tools such as the Immune Epitope Database (IEDB) integrate multiple predictive algorithms to determine optimal binding motifs across diverse HLA alleles, facilitating broad epitope screening.15 Alternatively, mass spectrometry-based HLA ligandomics enable the direct identification of endogenously processed peptides presented on tumor cells, revealing not only canonical epitopes but also those derived from overexpressed proteins, signal peptides, or somatic mutations.148 This approach can be integrated with functional genomics and bioinformatic annotations to pinpoint both TAAs and TSAs, including neoantigens. Notably, ligandome analyses often uncover peptides of noncanonical lengths (e.g., 11–13 amino acids), which may fall outside the predictive scope of conventional motif-based algorithms.149Despite their potential for eliciting targeted antitumor T-cell responses, peptide-based vaccines face inherent challenges, such as poor stability, short half-life, and limited immunogenicity.150,151 To overcome these barriers, peptides are frequently co-formulated with adjuvants—including cytokines, saponins, emulsions (e.g., Montanide), Toll-like receptor (TLR) agonists such as CpG-ODNs, and particulate delivery systems (e.g., liposomes, PLGA nanoparticles, and exosomes).152 These carriers enhance peptide stability, promote uptake by APCs, and stimulate innate and adaptive immunity. Additional strategies include peptide engineering, such as amino acid substitutions to strengthen MHC binding or T-cell receptor engagement, yielding heteroclitic variants with enhanced immunogenicity and an ability to circumvent immune tolerance.153,154 Another innovative avenue exploits antigenic molecular mimicry, wherein microbial antigens bearing structural homology to TA are employed to induce cross-reactive T-cell responses, leveraging preexisting immunity against pathogens for antitumor effects.155,156,157 While preclinical and early clinical results are promising, achieving robust and durable clinical efficacy will require further refinement of delivery platforms, adjuvant combinations, and patient-specific epitope selection.158,159Personalized DC cancer vaccinesDCs originate from bone marrow progenitors and circulate in the bloodstream as immature precursors before homing to peripheral tissues.83 Within these tissues, they undergo differentiation and become actively engaged in capturing, processing, and presenting antigens via MHC molecules. Upon receiving appropriate stimuli, DCs mature and migrate to secondary lymphoid organs, where they present antigenic peptides to T cells and initiate adaptive immune responses.85,86 DCs can be generated in vitro from CD34+ hematopoietic precursors under the influence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) or from monocytes cultured with GM-CSF and interleukin-4 (IL-4).87 Recognized for their ability to prime tumor-specific T cells, personalized tumor antigen-pulsed DCs have emerged as promising vehicles for cancer immunotherapy.84,160Various strategies have been developed to load DCs with personalized tumor antigens ex vivo, including the use of autologous tumor-derived peptides or proteins, nucleic acids (RNA or DNA), necrotic tumor cells, chaperone proteins, exosomes, and autologous tumor-cell-DC hybrids. DC-based vaccines administered via intravenous, intradermal, subcutaneous, intranodal, or intratumoral routes aim to initiate and modulate antigen-specific immunity.88,161 For example, in DC-autologous tumor-cell fusion vaccines, DCs phagocytose apoptotic tumor cells and acquire neoantigens through membrane fusion. Short peptide antigens (9–15 amino acids) are presented on MHC class I molecules and efficiently activate tumor-specific CD8+ CTLs.162 Alternatively, extracellular protein antigens are typically presented via MHC class II but can also access the MHC class I pathway through cross-presentation.163 The efficiency of antigen cross-presentation depends on the antigen formulation, delivery method, and structural properties.164,165 Electroporation has proven effective for loading various antigen formats (e.g., mRNA or proteins) into DCs, promoting robust cross-presentation and inducing antigen-specific CTL responses. Once antigen-loaded, immature DCs migrate to secondary lymphoid organs, where they present processed antigens to helper and cytotoxic T cells, triggering specific immune activation.166 DC-based vaccines are inherently personalized and can be tailored to incorporate both TAAs and neoantigens, thereby eliciting potent patient-specific immune responses. These vaccines have demonstrated promising safety and efficacy in treating solid tumors.167,168 Antigen loading can be achieved through multiple methods, such as pulsing with synthetic peptides, whole-tumor mRNA, autologous tumor lysates, or fusion with tumor cells. Tumor lysates, in particular, enable the presentation of a diverse antigen repertoire independent of HLA restriction, as illustrated by the FDA-approved sipuleucel-T for prostate cancer, which uses autologous APCs pulsed with a recombinant fusion protein containing prostatic acid phosphatase.40,169 Similarly, tumor lysate-pulsed DC vaccines offer broader application potential for glioma patients than peptide-pulsed vaccines, as they are not constrained by HLA specificity.170,171Despite these advances, key challenges remain. Optimal antigen formats, long peptides, mRNA, proteins, or whole lysates have yet to be definitively established for DC loading.172 Furthermore, factors such as DC maturation status, route of administration, and the ability to prime T cells within lymph nodes and the TME significantly influence vaccine efficacy. Ongoing research and clinical trials are essential to address these hurdles, but DC-based vaccines continue to represent a highly promising avenue for future cancer immunotherapy.173,174Personalized tumor-cell-based cancer vaccinesThe utilization of tumor cells as a source of antigen offers significant advantages due to their ability to present a whole repertoire of TAAs and neoantigens, which collectively facilitate the induction of potent and multifaceted antitumor immune responses.16 This comprehensive antigenic profile surpasses the limitations of single-antigen vaccines by minimizing immune escape caused by tumor heterogeneity and antigen loss. Representative strategies leveraging this approach include whole-tumor cells, tumor-cell lysates, and tumor-cell membranes, each preserving a diverse set of antigens capable of eliciting both CD8+ and CD4+ T-cell responses through MHC class I and II presentation.175 Furthermore, such platforms inherently contain DAMPs and other immunostimulatory molecules that enhance dendritic cell maturation and antigen cross-presentation, thereby promoting sustained T-cell activation and memory formation.176 By engaging a wide range of immune specificities, these tumor-cell-based vaccines stimulate a robust and adaptive immune attack against tumor cells, underscoring their potential as powerful tools in personalized cancer immunotherapy.Irradiated whole autologous tumor-cell vaccines were among the first personalized vaccine platforms tested clinically.81 These vaccines theoretically present the entire repertoire of a patient’s tumor antigens, including both known shared antigens and unique neoantigens, thereby maximizing the potential for inducing a broad and polyclonal T-cell response. Similarly, vaccines based on tumor-cell lysates, where surgically resected tumor tissue is processed into a homogenate containing intracellular and membrane-associated components, offer a comparable antigenic breadth.170 In addition, the tumor-cell membrane (TCM), which contains a sizable portion of cancer cell information, is one of the key initiators of antitumor immunity, and this principle extends to whole cells and lysates.177 Generally, these tumor-derived materials are taken up by DCs and degraded via proteasomes in the cytosol. After assembling the antigen fragments with the class I MHC α and β2 m chains in the endoplasmic reticulum, DCs present peptide-loaded MHC-I complexes on their surfaces, activating multiple specific CD8+ T cells to annihilate tumor cells (Fig. 3). This leads to the stimulated release of further tumor antigens and DAMPs, which can be captured by other DCs, creating a self-amplifying cycle of antigen release and immune activation known as the tumor killing cascade, which is constantly augmented until tumor clearance.178 Multiple specific T-cell immunity sessions triggered by such broad-antigen vaccines reduce the incidence of immune tolerance and escape created by tumor heterogeneity and antigenicity more than vaccines containing a single or a few antigens.179 More importantly, the surgical acquisition of a patient’s tumor tissue is therefore a critical first step that holds profound significance for the entire paradigm of personalized cancer vaccination.180 This procedure provides the unique, patient-specific antigenic blueprint required to manufacture vaccines based on whole cells, lysates, or purified membranes. The fresh tumor specimen is not merely a source of antigens but a biological record of the individual’s tumor immunophenotype, its immunosuppressive landscape, and its neoantigen profile. This makes surgical resection more than a debulking procedure; it becomes an essential act of biosampling that enables the creation of a truly bespoke therapeutic agent designed to target the residual and metastatic disease that often remains after surgery.79However, despite their conceptual appeal and demonstrated efficacy in animal models, first-generation whole autologous tumor-cell or tumor-cell lysate vaccines universally failed to significantly prolong the median overall survival of patients with different cancers in clinical trials.181 One of the possible reasons for this failure is that the abundance of regulatory factors in immunology and metabolism remodels the TME and impedes antitumor immunity, a plausibly more critical reason than patient heterogeneity and study design flaws.182 This is a fundamental challenge intrinsic to using crude tumor material. The very completeness of the antigenic source also means it contains a repertoire of molecules that facilitate immune escape.183 A large number of studies have revealed that tumor-derived materials, including tumor-derived extracellular vesicles (TEVs) present in lysates, can inhibit T-cell activation via PD-L1, IL-10, prostaglandin E2, and Fas-L and promote Treg proliferation by activating the TGF-β/SMAD pathway. TEVs also carry ligands for NKG2D and TGF-β, which hinder the cytotoxicity of NK cells and drive M2 macrophage polarization.184,185 Apart from immune interference, tumor-derived vesicles have been revealed to accelerate tumor angiogenesis via the transfer of tumor cargoes to endothelial cells. Furthermore, tumor cells contain many self-antigens common to normal cells, raising the risk of the mobilization of CTL responses to normal tissues.186It is against this backdrop of both immense promise and a significant challenge that the field has advanced toward more refined approaches such as TCM-coated NPs.187 The TCM vaccine strategy seeks to harness the broad antigenic profile of the whole cell or lysate while attempting to mitigate its immunosuppressive drawbacks through engineering and purification. As TCM vaccines are usually loaded onto NPs, their biocompatibility mainly depends on the nanocarrier.93 The biosafety of NPs is affected by their physicochemical properties, such as size, structure, shape, aggregation state, surface chemistry, and stability.17 Compared with other types of modified NPs, NPs with a TCM coating provide significant advantages: they do not change the size of the core NP significantly, which is crucial as different cells prefer to take up NPs of distinct sizes (e.g., DCs usually ingest virus-like particles of 20–200 nm, while macrophages prefer larger ones of 0.5–5 µm).188,189 The TCM coating can maintain DC uptake efficiency by controlling the size of NPs.190 Second, TCM provides a larger platform for surface engineering and serves as a barrier to some toxic metal ions from the NP core. Third, TCM changes the charge of NPs, which effectively reduces nonspecific uptake by nonimmune cells.191 In addition, TCM naturally targets tumor tissue, which elevates the efficiency of APC uptake in the tumor microenvironment. Finally, and most importantly, TCM provides a multifaceted antigenic source to trigger antitumor immunity.192 However, compared with TCM-wrapping NPs, whole cells or lysate-derived TEVs supply DAMPs and intracellular tumor antigens, which can trigger stronger innate immunity and expand the spectrum of antitumor immunity, highlighting a trade-off between antigenic completeness and safety.92Obstacles to personalized antitumor vaccine developmentDespite significant advancements in NGS and AI-driven epitope prediction algorithms, substantial challenges persist in consistently activating polyfunctional T-cell populations capable of sustaining long-term immunological effects.23 While certain personalized antitumor vaccines have yielded positive outcomes in clinical trials, no personalized vaccine has yet received FDA approval. Table 1 summarizes selected clinical trials of personalized antitumor vaccines, highlighting both positive and negative results. In what follows, we examine the fundamental obstacles to personalized antitumor vaccine development, focusing on immunological mechanisms (Fig. 4).Fig. 4Full size imageImmunological perspectives of obstacles to personalized cancer vaccine efficacy. The efficacy of personalized cancer vaccines is constrained by multiple immunological challenges. First, the immunosuppressive tumor microenvironment fosters immune evasion through dominant regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and cytokines (e.g., TGF-β, IL-10), compounded by physical barriers such as fibrosis and abnormal vasculature that hinder immune cell infiltration. Second, tumor heterogeneity, driven by clonal evolution and genomic instability, generates intratumoral and intertumoral antigenic variability, with dynamic antigen loss or downregulation enabling immune escape. Third, failed integration of the immune response network arises from insufficient dendritic cell-mediated antigen presentation, poor T-cell priming, and disrupted crosstalk between innate and adaptive immunity, including weak costimulatory signals and checkpoint inhibition. Finally, inadequate immunological memory formation reflects impaired generation or maintenance of long-lived memory T-cell subsets (central and effector memory) due to dysfunctional survival signals (e.g., IL-10, IL-15) and compromised T helper cell support (Created with Adobe Photoshop)Immunosuppressive TMEThe TME poses significant challenges to the development of efficacious personalized cancer vaccines by fostering an immunosuppressive landscape that undermines antigen presentation and adaptive immune responses. One major hurdle lies in its spatial and temporal heterogeneity, which drives clonal evolution and antigenic diversity within and across tumors.193 This variability complicates the identification of stable, immunodominant neoantigens for vaccine design, as tumor cells dynamically alter their antigenic profiles under selective pressures, such as immune checkpoint inhibitor therapy or chemotherapy.194 Furthermore, the TME harbors immunosuppressive elements, such as regulatory T cells, myeloid-derived suppressor cells, and inhibitory cytokines (e.g., transforming growth factor-beta [TGF]-β, interleukin [IL]-10), which suppress DC maturation and cytotoxic T-lymphocyte (CTL) activation even when vaccines successfully prime tumor-specific immunity. Physical barriers, such as the dense extracellular matrix and abnormal vasculature, further limit vaccine-induced T-cell infiltration, while metabolic competition, mediated by lactate accumulation and hypoxia, impairs T-cell function through adenosine signaling and programmed death ligand 1 (PD-L1) upregulation.195,196 These interconnected mechanisms create a self-reinforcing ecosystem that resists vaccine-mediated immune surveillance. The dynamic remodeling of the TME further perpetuates therapeutic resistance through spatially heterogeneous metabolic reprogramming and sustained activation of immune checkpoint networks.37While personalized vaccines aim to target patient-specific neoantigens, the TME often promotes immune tolerance via mechanisms, such as defective antigen processing and presentation machinery (e.g., downregulation of human leukocyte antigen [HLA] class I molecules).197 Additionally, tumor-associated macrophages and fibroblasts actively scavenge and degrade extracellular neoantigens, reducing their availability for cross-presentation by DCs.198,199 The TME microbiota adds another layer of complexity, as the intestinal and intratumoral microbiota can modulate systemic immune responses. For instance, Helicobacter pylori infection enhances or diminishes immunotherapy efficacy depending on the cancer type, suggesting that microbiota profiling should be integrated into vaccine personalization strategies.200 Even when vaccines successfully activate tumor-specific T cells, the TME’s immunosuppressive checkpoints (e.g., CTLA-4, T-cell immunoglobulin mucin 3) and enzymatic networks (e.g., indoleamine 2,3-dioxygenase, arginase 1) rapidly induce T-cell exhaustion, undermining durable antitumor immunity.201,202Tumor heterogeneityTumor heterogeneity spans both the spatial and temporal domains.203,204 This dynamic multilevel phenomenon encompasses intercancer variability, interindividual genomic divergence within histologically identical malignancies, molecular discrepancies between primary and metastatic foci, and intraparenchymal heterogeneity in multifocal primary tumors and culminates in subclonal architectural complexity within individual neoplastic masses. Temporal heterogeneity mirrors the evolutionary progression of neoplastic clones, driven by cumulative genetic and epigenetic alterations that fuel phenotypic diversification during tumor progression.205 This dual-axis complexity critically challenges conventional immunotherapeutic approaches via two synergistic mechanisms.63,206 First, current immunotherapies show inherent limitations in achieving comprehensive target saturation across dynamically evolving tumor populations. Second, traditional neoantigen prediction approaches, depending on single-region biopsies, inadequately map the tumor’s mutational topography, generating incomplete clonal mutation profiles and compromising neoantigen targeting precision.207 The dual-layered heterogeneity complicates neoantigen screening and leads to substantial variance in tumor antigen-binding affinities and immune reactivities across patients, ultimately dictating both the initiation and magnitude of antitumor immune responses.208 These biological constraints necessitate highly personalized immunotherapeutic strategies and explain why current neoantigen-based interventions remain patient-specific and why universal neoantigen vaccine development faces formidable translational barriers.209,210Failure to establish an integrated immune response networkThe tumor-immune interface functions through a complex, multilayered defense system consisting of three interdependent components:211 (1) cellular effectors, including CD8+ CTLs, natural killer cells, and γδ T cells; (2) antigen-presenting sentinels, such as DC subsets and B lymphocytes; and (3) molecular coordinators, comprising cytokines, such as interferon-gamma (IFN-γ), IL-12, and TGF-β family members. This triadic system operates through feedforward activation loops and negative feedback mechanisms to sustain immune homeostasis. CD8+ T cells mediate antigen-specific cytotoxicity by releasing perforin and granzymes and through FAS/FAS-L interactions. Concurrently, CD4+ T follicular helper cells regulate germinal center reactions to facilitate affinity-matured antibody production.212 DCs utilize cross-presentation to load tumor-derived peptides onto MHC class I molecules, a process that is enhanced by danger signals, such as high mobility group box 1 and adenosine triphosphate released during immunogenic cell death.213 Macrophages exhibit a spectrum of polarization states: the M1 phenotype secretes proinflammatory cytokines, including IL-1β and tumor necrosis factor-alpha, and presents antigens via MHC class II, whereas the M2 phenotype produces IL-10 and vascular endothelial growth factor to facilitate angiogenesis and tissue remodeling.214 The evolutionary rationale for this integrated network manifests in three main principles: (1) combinatorial antigen recognition through TCR–MHC and B-cell receptor–epitope interactions minimizes immune evasion via clonal selection,215 (2) spatiotemporal coordination via chemokine gradients (CXCL9/10/11) ensures leukocyte infiltration into tumor nests,216 and (3) epigenetic reprogramming of memory T/B cells establishes durable immunosurveillance.217Current neoantigen vaccine platforms face two fundamental immunological constraints that critically impair therapeutic efficacy. First, the predominant focus on MHC class I-restricted epitopes creates an imbalanced adaptive immune response.218 While CD8+ CTLs are effectively primed through direct MHC-I/peptide–TCR interactions, the absence of MHC class II-restricted epitopes prevents CD4+ helper T-cell engagement.219 This deficiency disrupts critical licensing mechanisms: CD4+ T cells provide IL-2 and IL-21 cytokines sustaining CTL proliferation, CD40/CD40L signals for DC maturation and cross-priming capacity, and cognate help for B-cell affinity maturation in germinal centers.220 A recent study revealed that when tumor-reactive CD4+ and CD8+ T cells form “immune triads” together with APCs, tumor-specific CD4+ T cells prevent and reverse tumor-specific CD8+ T-cell dysfunction in solid tumors.221 In patients with pleural mesothelioma treated with immune checkpoint blockade therapy, these immune triads are associated with clinical response.221 A second critical limitation stems from the frequent omission of adjuvant components in neoantigen vaccine formulations, which fundamentally undermines innate immune system engagement. The absence of pathogen- or damage-associated molecular pattern agonists prevents the activation of conserved immune signaling pathways, particularly TLR, STING, and NLRP3 inflammasome cascades, in APCs.222 This deficiency results in insufficient upregulation of costimulatory surface markers and chemokine secretion, impairing DC maturation and migration to secondary lymphoid tissues.223 The lack of coordinated innate–adaptive immune crosstalk manifests as defective cross-presentation to CD8+ T lymphocytes and suboptimal T helper 1 polarization, ultimately compromising the magnitude and durability of antitumor immunity.Inadequate immunological memory formationThe establishment of long-term immunological memory is fundamental to the success of cancer immunotherapies because it determines the durability of therapeutic efficacy and prevents tumor recurrence. The establishment of durable immunological memory, primarily mediated by specialized subsets of memory lymphocytes, enables antigen-specific recall responses that are critical for oncological protection. Central, effector, and tissue-resident memory T cells form compartmentalized surveillance networks, whereas memory B-cell pools comprising long-lived plasma cells and quiescent memory B-cell subsets preserve humoral recognition capacity. This coordinated cellular memory architecture facilitates rapid neoantigenic rechallenge responses through MHC-restricted cytotoxic effector mechanisms and high-affinity antibody production, thereby establishing sustained immunosurveillance capable of eradicating minimal residual disease and preventing subclinical recurrences.224 In adoptive cell therapies, such as CAR-T or checkpoint inhibitors, the persistence of memory T cells correlates strongly with prolonged clinical remission, as these cells retain the capacity to recognize tumor neoantigens and initiate cytotoxic cascades without requiring repeated therapeutic intervention.225 For instance, anti-PD-1/PD-L1 therapies enhance memory T-cell formation by blocking inhibitory signals, allowing clonal expansion of tumor-reactive T cells and their differentiation into long-lived central memory subsets.226 Similarly, cancer vaccines aim to prime naïve T cells into memory populations through DC-mediated antigen presentation, ensuring that even minimal residual disease can be targeted years after initial treatment.227 This memory-driven durability is particularly critical in malignancies with high heterogeneity or metastatic potential, in which latent tumor cells may evade initial immune attacks but remain vulnerable to memory-driven eradication.228Generating robust antigen-specific memory remains elusive for personalized cancer vaccines because of the intrinsic challenges posed by tumor antigen biology. Tumors exhibit clonal heterogeneity and Darwinian selection, leading to the rapid evolution of antigen-loss variants that evade vaccine-targeted epitopes.229 Even when immunogenic neoantigens are identified, their low abundance or structural mimicry of self-antigens often prevents overcoming the immune tolerance thresholds required for memory differentiation. Antigen-processing inefficiencies further compound this issue; defects in proteasomal cleavage or HLA class I presentation prevent optimal epitope display, while tumor-intrinsic mechanisms, such as β2-microglobulin mutations, disrupt antigen-MHC complex stability.230 Additionally, the time lag between neoantigen identification and vaccine delivery allows tumors to acquire secondary mutations, rendering selected antigens obsolete even before immunization begins.231Personalized cancer vaccine platforms and delivery systemsNonnanomaterial platformsNaked mRNANaked or nonformulated mRNA vaccines consist of mRNA molecules dissolved in a buffer solution and are administered via direct injection of the aqueous formulation (Fig. 5).10 Although these vaccines cannot passively cross cell membranes, multiple mechanisms have been proposed to explain their cellular uptake. One widely supported hypothesis involves the internalization of naked mRNA by DCs through macropinocytosis. This process enables the translation of encoded antigens, promotes DC maturation, and subsequently activates antigen-specific T-cell responses.232,233 Following activation, the mRNA is rapidly metabolized within the cells. Alternative uptake mechanisms include membrane disruption strategies such as direct penetration, exemplified by microinjection, a technique dating back to the 1970s,234 or permeabilization methods such as electroporation,235 mechanical disruption, thermal ablation, optoporation, and the use of biochemical agents or gated channels.236 Notably, intranodal administration of nonformulated mRNA represents a promising strategy for direct antigen delivery to antigen-presenting cells residing in lymph nodes,237 thereby bypassing the need for DC migration and enhancing T-cell priming efficiency.232 Several studies have demonstrated that intranodally injected naked mRNA is efficiently taken up by DCs and induces potent antitumor T-cell immunity.122 Commonly used solvents for naked mRNA vaccines include Ringer’s solution and lactated Ringer’s solution, both of which contain calcium, a known enhancer of mRNA uptake.238 These formulations have been extensively evaluated in preclinical and clinical contexts. For instance, repeated intranodal administration of naked mRNA in mice induced de novo T-cell priming, resulting in the generation of cytolytic effector T cells capable of trafficking to lymphatic tissues and establishing memory responses.239 Similarly, intradermal injection of mRNA dissolved in lactated Ringer’s solution has been shown to activate TLR7/8 pathways, leading to enhanced cytokine production and robust innate and adaptive immune activation.240 Clinical trials have further validated this approach; direct injection of mRNA in Ringer’s solution into lymph nodes elicited multispecific T-cell responses against vaccine neoepitopes, with evidence of T-cell infiltration and tumor-cell killing observed in resected metastases from vaccinated patients.10Fig. 5Full size imagePersonalized cancer vaccines based on nonnanomaterial platforms. Various nonnanomaterial platforms for personalized cancer vaccine delivery have been developed, including the use of naked mRNA, mRNA‒protein complexes, physical mixtures of antigens and adjuvants, viral and bacterial vectors, and live cell platforms. Key approaches involve enhancing mRNA stability and uptake through techniques such as intranodal injection of naked mRNA, CPPs, and engineered carriers, which promote rapid antigen production and efficient endosomal escape. Synchronous uptake of antigens and adjuvants by APCs, particularly DCs, facilitates robust APC activation and neoantigen presentation, ultimately inducing adaptive immune responses. Other platforms, such as pulsed live cells, further expand the versatility of personalized cancer vaccine design (Created with Adobe Photoshop)The advantages of naked mRNA vaccines include their inability to integrate into the host genome, thereby improving safety profiles, and their direct translation in the cytosol, which obviates the need for nuclear entry, a requisite for DNA vaccines, enabling rapid protein expression and accelerated immune activation.125 Additionally, localized antigen expression at the delivery site improves targeting specificity, and mRNA platforms generally exhibit favorable tolerability with reduced toxicity and immunogenicity compared with DNA-based systems. Nevertheless, a key limitation remains the susceptibility of naked mRNA to degradation by extracellular RNases.241,242 This instability can be partially ameliorated through optimized routes of administration, such as intradermal, intranodal, or intramuscular injection, which minimize exposure to serum nucleases, as well as through chemical modifications that enhance mRNA stability and diminish immunogenicity.243Peptide-based delivery systemsProtamine has been extensively explored in early mRNA vaccine delivery systems, particularly in the context of personalized mRNA cancer vaccines (Fig. 5). By spontaneously condensing mRNA through electrostatic interactions, protamine protects the encapsulated mRNA from degradation by extracellular RNases. Additionally, protamine-mRNA complexes function as adjuvants by activating TLR7/8 and promoting a Th1-type immune response, which is critical for antitumor immunity.244 However, the suboptimal translation efficiency of protamine-based complexes is often attributed to excessively tight binding between the peptide and mRNA, which hinders ribosomal accessibility.38 This issue has been addressed through the development of RNActive® by CureVac AG, a two-compartment formulation that combines protamine-complexed mRNA (50%) with unformulated antigen-encoding mRNA (50%).245 In this system, the protamine-bound component serves as an immune stimulant, while nucleoside-modified mRNA enables efficient antigen production. Currently, RNActive® vaccines encoding TAAs are under investigation in multiple phase I/II clinical trials for various solid tumors.246 These vaccines have been generally well tolerated, show robust immunogenicity, and demonstrate moderate antitumor efficacy in some patients, highlighting their potential for personalized oncological applications in TSA integration.247,248Beyond protamine, cationic cell-penetrating peptides (CPPs) represent another promising class of carriers for RNA delivery in personalized cancer vaccines. CPPs are a class of linear or branched peptide chains typically composed of 5–30 amino acid residues that are capable of crossing the plasma membrane. Their structures may contain nonprotein amino acids (such as ornithine) or chemically modified amino acid residues. These modifications help enhance endocytic escape, reduce degradation by endocytic enzymes, and alter the net charge of peptide molecules, but their basic sequences are mainly composed of standard protein amino acids.249 Although their cellular internalization mechanisms are not fully elucidated, CPPs are hypothesized to facilitate clustering of negatively charged glycosaminoglycans on the cell surface, triggering macropinocytosis.250 For instance, the RALA peptide, an amphipathic, arginine-rich CPP with a structural segregation of charged and neutral residues, has been shown to condense mRNA and facilitate its delivery into DCs.251 Intradermal injection of DCs loaded with RALA-mRNA complexes elicited potent antigen-specific cytolytic T-cell responses, underscoring their utility in adoptive cell therapy and vaccine strategies.252,253 Other peptides, such as a D-amino acid-based truncated protamine fused to the short CPP Xentry, were utilized to deliver CFTR mRNA in epithelial cells.254 For example, the α-helical cationic CPP KALA was integrated into vitamin E-based lipid nanoparticles (ssPalmE-LNPs) to enhance mRNA expression and proinflammatory cytokine secretion in DCs, providing a robust ex vivo DC-based vaccine system.255 Similarly, Zhang et al. developed cholesterol-modified DP7, a cationic peptide with inherent immunoadjuvant properties, to functionalize DOTAP liposomes. The resulting DOTAP/DP7-C liposomes mediated efficient mRNA transfer into DCs in vitro, and subcutaneous administration of neoantigen-encoding mRNA formulated with these particles significantly inhibited the growth of LL2 tumors in vivo, illustrating a promising platform for personalized mRNA vaccines.256 In addition to cationic CPPs, anionic peptides such as GALA have also been employed as functional ligands that can be conjugated to LNPs or polyplexes via click chemistry to enhance cellular uptake and mRNA delivery efficiency, further expanding the pathway for personalized cancer immunotherapies.257Physical mixturePersonalized cancer vaccines formulated as a physical mixture comprise patient-specific antigenic components, such as neoantigen peptides or nucleic acids encoding them, blended with an adjuvant through simple physical combination rather than chemical conjugation or coencapsulation (Fig. 5).258 This modular strategy enables the codelivery of antigens and immune stimulants within a single formulation without complex fabrication processes, thereby supporting flexible and rapid personalization.259 Immunologically, the effectiveness of such vaccines depends critically on the concurrent uptake of both elements by APCs, particularly DCs, at the administration site. Upon injection, adjuvants, such as TLR agonists, cytokines, or saponin-based compounds, induce local inflammation and enhance DC activation, which in turn augments antigen uptake, processing, and presentation.260 The antigens, whether in the form of peptides or mRNA, are internalized and presented via both MHC class I and II pathways, stimulating polyfunctional CD8+ and CD4+ T-cell responses. This leads to the priming and expansion of tumor-specific T cells capable of migrating to and eliminating cancer cells that express the corresponding neoantigens. The ability to tailor the adjuvant-to-antigen ratio and select appropriate immune potentiators offers further opportunities to modulate immune polarization toward desired effector profiles. Notably, newer generations of highly purified adjuvants, such as Montanide ISA-51 and ISA-720, have been developed to reduce toxicity while maintaining immunogenicity. Peptide vaccines formulated with these adjuvants have demonstrated the capacity to elicit robust antibody titers and sustained effector T-cell responses.261,262,263A major advantage of the physical mixture platform lies in its straightforward manufacturing and scalability. Because antigens and adjuvants are produced and validated independently, the formulation process is simplified, which helps minimize regulatory complexities and accelerate clinical application, an essential consideration for patient-specific therapies where timelines are critical.264 Moreover, employing well-established adjuvants allows researchers to leverage extensive prior safety and efficacy data. However, a significant challenge associated with this approach is the potential for inconsistent distribution or divergent biodistribution of the antigen and adjuvant, which may impede colocalization within the same APCs and diminish vaccine potency. Additionally, without protective carriers or targeted delivery systems, naked antigens are susceptible to rapid degradation and suboptimal cellular uptake, underscoring the need for improved delivery strategies or alternative administration routes.265 Despite these limitations, ongoing innovations in adjuvant design and formulation technology are steadily enhancing the stability, delivery efficiency, and immunogenicity of physical mixture-based vaccines, affirming their continued relevance in the advancing field of personalized cancer immunotherapy.266Engineered viral and bacterial vectorsThe development of personalized cancer vaccines has markedly advanced with the implementation of engineered viral and bacterial vectors, which enable efficient delivery and potent immunostimulation tailored to individual tumor mutational profiles. These vectors are designed to encode patient-specific neoantigens, unique proteins derived from somatic mutations identified via genomic sequencing, and aim to elicit robust, targeted antitumor immune responses (Fig. 5).267 Viral vectors, including adenoviruses, poxviruses, vesicular stomatitis virus (VSV), and lentiviruses, represent extensively investigated platforms owing to their high transduction efficiency, broad cellular tropism (particularly toward dendritic cells), and inherent adjuvant properties mediated through pathogen-associated molecular patterns. For example, recombinant adenoviral vectors can efficiently deliver neoantigen sequences into antigen-presenting cells, inducing strong CD8⁺ T-cell responses critical for tumor control.268 Similarly, modified vaccinia Ankara (MVA) and other poxviral vectors have been engineered to express multiple neoantigens and are frequently employed in heterologous prime-boost regimens to circumvent preexisting immunity and enhance T-cell priming.269,270 More recently, oncolytic viruses such as talimogene laherparepvec (T-VEC), originally developed for direct tumor lysis, have been repurposed to deliver neoantigen transgenes, thereby merging direct oncolysis with antigen-specific immunization.271Although less clinically advanced in oncology than viral platforms, bacterial vectors provide distinctive advantages for both mucosal and systemic vaccination approaches.272 Attenuated strains of Listeria monocytogenes, Salmonella typhimurium, and Escherichia coli can be genetically modified to deliver antigen-encoding plasmids or recombinant proteins directly to antigen-presenting cells within mucosal or lymphoid tissues.273 Listeria, in particular, has demonstrated considerable promise due to its ability to enter the cytoplasm of host cells via lysosomal escape and stimulate both MHC class I and II pathways, promoting potent CD8⁺ and CD4⁺ T-cell activation.274 For instance, Redenti et al. engineered the probiotic Escherichia coli Nissle 1917 as an antitumor vaccine platform optimized for enhanced production and cytosolic delivery of neoepitope peptides, with increased susceptibility to blood clearance and phagocytosis. These modifications improve both safety and immunogenicity, resulting in a system that stimulates potent and specific T-cell-mediated anticancer immunity, effectively controlling or eliminating tumor growth and prolonging survival in murine models of advanced primary and metastatic solid tumors.275 Tumor antigens delivered via bacterial vectors can be presented either anchored to the bacterial outer membrane or secreted into the extracellular environment. For example, antigenic short peptides can be displayed on the membrane of outer membrane vesicles (OMVs) secreted by Escherichia coli using the bacterial membrane protein lysocytin A (ClyA).276 Alternatively, antigenic peptides can be conjugated to bacterial OMVs via biochemical methods, as demonstrated by Cheng et al.,277 who coupled the OT1 peptide to a ClyA-SpC/SnC fusion protein using a plug-display system. Additionally, live bacterial vectors such as attenuated Listeria monocytogenes and Listeria ivanovii can be modified to secrete tumor antigens, e.g., the HPV16 E6E7 fusion protein, within infected host cells.278 Engineered bacteria can also induce inflammatory cytokines and remodel the TME, further supporting their use as in situ cancer vaccines.279 Meanwhile, bacterial ghosts (nonviable cell envelopes) and minicell-based systems provide alternative strategies for the safe and efficient delivery of multiple neoantigens without the risks associated with live infection.280The principal advantages of pathogen-based vectors include their inherent immunogenicity and well-established molecular biology, which facilitate rapid cloning and production of personalized vaccine constructs.281 Their natural tropism for immune cells and inherent activation of innate immunity via pattern-recognition receptors often reduce or eliminate the need for exogenous adjuvants. However, significant challenges remain.282,283 Preexisting immunity to common viral vectors, such as adenovirus serotype 5, can diminish vaccine efficacy by accelerating vector clearance before sufficient antigen expression occurs. Similarly, antibiotic use or prior immune exposure may limit the utility of bacterial vectors. Safety concerns, including off-target effects and potential inflammatory toxicity, also require careful management. Moreover, the manufacturing timeline for personalized recombinant viral or bacterial vaccines, typically involving cloning, amplification, and purification, is generally longer than that of mRNA or peptide-based platforms, posing logistical challenges for timely administration in patients with advanced cancers.284,285Live cell platformsThe emergence of live cell-based platforms represents a sophisticated and biologically nuanced approach within the field of personalized cancer vaccines (Fig. 5). In contrast to acellular vectors or synthetic nanomaterials, these systems utilize whole cells, either autologous (patient-derived) or allogeneic (from universal donors), as intelligent vehicles for antigen presentation or as bioactive factories capable of initiating and sustaining potent antitumor immune responses.286 By harnessing the inherent biological properties of living cells, these platforms facilitate the generation of robust, durable, and highly specific immune reactions tailored to the unique mutational landscape of an individual’s malignancy.287DC-based vaccines constitute the most well-established paradigm within this category. The canonical methodology involves isolating patient monocytes, differentiating them into DCs ex vivo, loading them with patient-specific tumor antigens, such as peptides, or RNA/DNA encoding neoantigens, and subsequently reinfusing the primed cells. These engineered DCs migrate to lymphoid organs, where they directly present antigenic peptides via MHC molecules to naïve T cells, thereby initiating a potent antigen-specific CTL response. The clinical success of Sipuleucel-T, an autologous cellular immunotherapy for prostate cancer, provided critical proof of concept for this approach. Contemporary strategies further enhance personalization by loading DCs with mRNA encoding patient-specific neoantigens, ensuring comprehensive presentation of the mutant proteome and broadening the immune attack.288 Additionally, DCs can be genetically modified to augment their immunogenicity, for example, through the expression of cytokines such as IL-12 or costimulatory molecules, thereby counteracting immunosuppressive tumor microenvironments and enhancing T-cell priming and persistence.289Beyond DCs, several other cell types are emerging as innovative vaccine platforms. Red blood cells (RBCs), or erythrocytes, exhibit particularly attractive features owing to their extended circulatory lifespan, inherent immunomodulatory properties that minimize self-reactivity, and their natural clearance mechanism in the spleen, a key lymphoid organ.290 Recent methodologies enable the engineering of RBCs to surface-display tumor antigens or to carry immunostimulatory payloads. Following infusion and eventual splenic sequestration, these modified RBCs facilitate efficient antigen transfer to splenic antigen-presenting cells, thereby promoting potent immune activation against target antigens. This strategy essentially employs a “hitchhiking” delivery mechanism that co-opts physiological pathways for effective immune education.291 Other promising live cell platforms include engineered macrophages and stem cells. For instance, mesenchymal stem cells (MSCs) exhibit natural tumor tropism and, when modified to express immunomodulatory cytokines or tumor antigens, can serve as targeted in vivo vaccines that home to tumor sites and provoke localized immune activation.292The principal advantage of live cell platforms lies in their unparalleled biological complexity and their capacity to engage the immune system multilaterally. They not only mediate antigen presentation but also supply essential costimulatory signals and cytokine environments often absent in synthetic systems, culminating in more robust and durable T-cell immunity.293 Nonetheless, significant challenges hinder their broad clinical translation. The manufacturing of autologous cell therapies remains complex, time-intensive, and costly, requiring specialized facilities and navigating stringent regulatory frameworks. Ex vivo manipulation may also compromise cellular functionality and viability. Allogeneic approaches, meanwhile, confront the persistent risk of host immune rejection. Despite these obstacles, ongoing advances in production standardization, ex vivo genetic engineering techniques, and the development of off-the-shelf allogeneic cell products are poised to mitigate current limitations, thereby reinforcing the integral role of live cell platforms in the future of personalized cancer immunotherapy.294Next-generation nanomaterial delivery systemsPersonalized cancer vaccines are developed using diverse antigen sources, including resected tumors, RNA/DNA derived from autologous tumor cells, and synthetic peptide/protein formulations of tumor-specific neoantigens. Additionally, autologous DCs can serve as critical components in personalized vaccine design by processing and presenting TAAs.23,53 While current therapeutic cancer vaccines demonstrate limited clinical efficacy compared to immune checkpoint inhibitors or adoptive T-cell therapies, significant advancements are being achieved through iterative optimization of vaccine compositions and delivery systems. Strategically engineered personalized vaccines aim to synergistically activate both innate and adaptive immunity, potentially establishing durable immunological memory.1Personalized cancer nanovaccines represent an interdisciplinary subclass of personalized cancer vaccines that exploit nanotechnology to enhance antigen delivery and nanoplatform intrinsic properties. These engineered vaccines encapsulate patient-specific neoantigens arising from tumor-specific nonsynonymous somatic mutations within nanostructured carriers, such as LNPs or polymeric particles, often codelivered with immunostimulatory adjuvants.60,295 Autologous tumor-cell membrane-coated nanovaccines contain the whole-tumor antigen profile.287 Personalized in situ cancer vaccines leveraging energy-producing agents to avoid the complicated in vitro vaccine preparation process can enhance tumor antigen release and processing by activating innate immune responses at the tumor site.296 For example, the delivery of pattern-recognition receptor agonists and virus/bacteria-derived materials and the delivery of agents that activate immunogenic cell death (ICD) have been explored as personalized in situ cancer vaccine strategies in preclinical studies.296Regarding their mechanisms of action, personalized nanovaccines exploit nanotechnology to optimize multiple stages of the cancer-immunity cycle (Fig. 6). First, nanocarriers protect antigens from degradation and facilitate targeted delivery to APCs, such as DCs, in lymphoid tissues. Upon uptake, nanoparticles (NPs) enhance antigen cross-presentation via MHC class I pathways, which is critical for CTL activation.94 Concurrently, nanovaccine adjuvants, such as TLR agonists, activate innate immunity by engaging pattern-recognition receptors on APCs, triggering nuclear factor κB-mediated production of proinflammatory cytokines (e.g., IL-12, IFN-γ) and upregulating costimulatory molecules (e.g., CD80/86) essential for T-cell priming.297 The simultaneous delivery of antigen and adjuvant via a single nanostructure ensures spatiotemporal coordination, promoting APC maturation and migration to LNs, where they prime tumor-specific T cells. Post-vaccination, nanovaccines induce epitope spreading, whereby initial CTL responses against vaccine-targeted neoantigens expand to include secondary tumor antigens not originally encoded in the vaccine. Epitope spreading partially addresses tumor heterogeneity through sequential activation of antigen-specific T-cell clones via de novo exposure to evolving neoantigen repertoires. This phenomenon, which has been observed in preclinical and clinical studies of neoantigen vaccines, diversifies the immune response and enhances heterogeneous tumor control by targeting antigenically distinct subclones.298,299 The nanostructured design further amplifies this effect by prolonging antigen retention in LNs and sustaining T-cell activation. Additionally, nanovaccines promote the generation of long-lived memory T cells, which provide durable protection against relapse by rapidly regenerating effector T cells upon tumor re-emergence.13Fig. 6Full size imageMajor components and mechanism of action of personalized cancer nanovaccine. Personalized cancer nanovaccines are engineered to target tumor-specific neoantigens and are delivered via multifunctional nanocarriers (e.g., lipid nanoparticles, polymeric nanoparticles, or cell-derived nanovesicles) that protect payloads and enhance lymphatic drainage to APCs. These nanovaccines coencapsulate immunostimulatory adjuvants (e.g., TLR agonists such as CpG oligonucleotides or STING activators) to amplify DC maturation and antigen presentation. Upon administration, nanocarriers facilitate APC uptake, endosomal escape, and cytosolic release of antigens, which are processed and loaded onto MHC-I/II molecules for CD8+/CD4+ T-cell activation. In addition, nanovaccines can be drained into LNs via lymph vessels by size effects. Adjuvants further enhance costimulatory signals (e.g., CD80/CD86) while blocking inhibitory pathways (e.g., PD-L1/PD-1 interactions via αPD-L1 antibodies), driving clonal expansion of antigen-specific CTLs. Activated CTLs infiltrate tumors, eliminating cells expressing cognate antigens, supported by CD4+ T cells and innate immune cells such as macrophages (Created with Adobe Photoshop)The evolution of personalized cancer vaccines has entered an important phase, with nanotechnology-enabled platforms redefining the fundamental principles of tumor immunogenicity and immune system engagement. In this section, we systematically review how advanced nanodelivery systems transcend traditional neoantigen-centric paradigms through four revolutionary principles: (1) expanding personalization beyond mutated peptide sequences to encompass patient-specific immune signatures, including tumor lysates, whole-tumor cells, or tumor-cell membranes, (2) spatiotemporal codelivery formulations that orchestrate antigen-adjuvant crosstalk, (3) multifunctional platforms enabling combinations with other therapies, and (4) systems-level innate–adaptive network integration (Fig. 7).Fig. 7Full size imageNext-generation nanomaterial-based personalized cancer vaccine delivery systems. We proposed an integrative strategy for personalized immune signature mapping and immunotherapy enhancement utilizing real-time tumor-cell membrane-coated NPs for codelivery of personalized TSAs and adjuvants. These engineered NPs, including self-adjuvant and hybrid membrane systems, enable real-time immune monitoring and modification of interventions based on previous treatments. The platform synergizes with chemotherapy drugs and ICIs, forming a combination immunotherapy approach that enhances nanovaccine potency and promotes systemic immune activation involving nanopotentiated DCs, CD8⁺ T cells, B cells, cytokine release, and innate immune responses (Created with Adobe Photoshop)Redefining personalization: from neoantigen peptide to immune signature mappingThe development of personalized cancer vaccines, while long anticipated as an important paradigm in oncology, continues to face substantial translational challenges rooted in the intrinsic limitations of conventional neoantigen-focused methodologies.1 Current clinical cancer vaccines predominantly employ computationally predicted neoantigens derived from tumor genome sequencing, necessitating resource-intensive synthesis of patient-specific formulations, including peptide cocktails, mRNA constructs, or DC vaccines loaded with predicted epitopes.21 Early-phase clinical trials have demonstrated partial success of such vaccines in generating tumor-specific T-cell responses.11 However, this framework suffers from three fundamental constraints: (1) bioinformatics pipelines systematically exclude critical antigenic determinants, such as post-translational modifications, alternatively spliced isoforms, and immunodominant TAAs of nonmutated origin; (2) the extended manufacturing timeline (typically 2–3 months from tumor biopsy to vaccine administration) is incongruent with the dynamic immune evolution observed in progressing malignancies300; and (3) prohibitive production costs create substantial healthcare disparities, particularly in resource-constrained settings.301 Emerging nanovaccine platforms using biomimetic engineering strategies provide a paradigm-shifting solution for these limitations. By employing tumor membrane coating technology, hybrid membrane systems, senescent cell-derived vesicles, or tumor lysate integration, these nanoscale architectures achieve three critical advancements: (1) preservation of native and comprehensive antigenic diversity through direct incorporation of tumor-derived components, (2) real-time immunological profiling of the patient’s disease status, and (3) dynamic antigen presentation mimicking physiological immune interactions.39 Their dual capacity for comprehensive antigen repertoire preservation and adaptive immune system engagement represents a fundamental improvement overprediction-dependent approaches, enabling true precision immunization that evolves synchronously with the patient’s immunological trajectory.The material science revolution extends to hybrid membrane systems that combine tumor-derived components with engineered biomimetics. Membrane-camouflaged nanotechnology achieves antigenic fidelity through bioinspired engineering of tumor-derived components, with tumor-cell membrane-coated NPs representing the archetype. This platform integrates autologous/allogeneic tumor plasma membranes onto synthetic nanocarriers, preserving the complete surface antigen continuum from conformationally intact TAAs and TSAs to posttranslationally modified glycoproteins and spatial antigen assemblies while retaining endogenous immunostimulatory molecules, such as damage-associated molecular patterns and calreticulin, which are essential for DC maturation. Pioneering work by Fang et al. demonstrated the translational potential of this approach. These researchers showed that MDA-MB-435 breast cancer cell membrane-derived NPs exhibited 40-fold enhanced DC uptake compared to erythrocyte-based counterparts and that using FDA-approved monophosphoryl lipid A (a TLR4 agonist) as an adjuvant synergistically enhanced IFN-γ secretion through optimized antigen processing and T-cell priming.302 Ye et al.303 developed a personalized nanovaccine by integrating PD-1 blockade with tumor membranes, leveraging real-time patient-derived antigen repositories for metastasis prevention, and promoting the development of other cancer cell membrane-coated NPs.177 In addition, Guo et al. developed cryogenically silicified tumor cells functionalized with pathogen-associated molecular patterns that act as potent cancer vaccines by enhancing antigen presentation and inducing tumor-specific T-cell immunity, leading to complete tumor eradication and synergizing with chemotherapy in resistant settings, with potential for room-temperature-stored personalized applications.304Next-generation tumor-cell membrane engineering extends to therapy-induced senescent tumor cells, whose upregulated MHC-I/II complexes and senescence-associated secretory phenotype factors enable endogenous adjuvant effects via senescence-associated secretory phenotype-mediated DC activation as well as CXCL10/CXCR3-axis-driven tertiary lymphoid expansion, achieving TME reprogramming without the need for exogenous adjuvants.305,306 Xu et al.307 developed a versatile platform for personalized postsurgical cancer immunotherapy by engineering cationic fluoropolymer-based nanovaccines. They coassembled a fluoropolymer with the model antigen ovalbumin (OVA) into stable NPs that exhibited dual immune activation. These nanocarriers not only facilitated efficient cytosolic delivery of antigens in DCs through membrane destabilization effects but also triggered robust TLR4-mediated signaling to enhance DC maturation. This synergistic mechanism enabled effective cross-presentation of TAAs to T lymphocytes, as systematically validated in experimental models.307Zhao et al.308 developed a nanovaccine based on polyethylenimine and autologous tumor-cell membrane protein antigens that stimulated innate immunity by activating the STING pathway. Go et al.309 engineered an innovative cancer nanovaccine by functionalizing tumor-cell membrane-derived NPs with monophosphoryl lipid A as a built-in adjuvant and integrating anti-CD28 antibodies through surface conjugation to enable dual-pathway T-cell activation. This biohybrid vaccine acts via DC-mediated antigen presentation in lymphoid tissues while simultaneously achieving direct T-cell engagement via CD28 costimulatory signaling, effectively bypassing conventional DC-dependent activation routes. The membrane-based nanoplatform demonstrated a unique capacity to prime tumor-specific CD8+ T-cell responses through both canonical and noncanonical immunological pathways, as validated in experimental models.309 This membrane engineering strategy established tumor-derived interfaces as versatile substrates for multimodal immunotherapeutic development.Other nanovaccine strategies, including tumor-cell membrane-coated aluminum phosphate NPs310 and functional DNA,311 have been developed for enhanced cancer vaccination by adding variable functions to vaccination. The self-adjuvating properties and antigen-loading flexibility of fluoropolymer carriers are promising for customized cancer immunotherapy regimens following tumor resection. Tumor lysate nanotechnology harnesses microfluidic chaotic mixing to encapsulate comprehensive antigen libraries spanning intracellular neoepitopes to mitochondrial antigens within stimuli-responsive nanocarriers equipped with multimodal biosensors tracking real-time immune dynamics (PD-1/PD-L1 flux, T-cell exhaustion markers, and cytokine networks).312 These emerging adaptive systems iteratively optimize antigen presentation through feedback-regulated release kinetics, achieving precision unattainable with conventional peptide vaccines.313The multidimensional personalization framework heralds a fundamental reconceptualization of individualized cancer immunotherapy. By transcending the reductionist approach of conventional peptide vaccines, which distill tumor complexity into algorithm-curated epitope subsets, next-generation nanovaccine platforms achieve holistic tumor-immune integration through concurrent preservation of complete antigenic diversity and bidirectional adaptation to host immunity.314 The strategic coencapsulation of tumor-derived antigens with immune-biosensing modules enables dynamic antigen presentation that evolves in synchrony with TCR repertoire remodeling and tumor immunoediting, effectively transforming static vaccine formulations into adaptive therapeutic systems.287 Clinically, such biological fidelity manifests as enhanced cross-presentation efficiency across heterogeneous HLA haplotypes through fluidic membrane protein mobility on NP surfaces, thereby overcoming the intrinsic HLA restriction bottleneck of peptide-based vaccines.315Manufacturing innovations further differentiate this paradigm by combining standardized tumor membrane harvesting protocols with lyophilized NP stabilization, shortening production timelines from the conventional 12–16 weeks to 3–4 weeks and reducing production costs via modular nanoscale fabrication.316 Rather than relying on static genomic inventories, therapeutic personalization dynamically incorporates spatially resolved antigenic topography, host immune kinetic profiles, and bidirectional tumor-immune coevolution trajectories.302 As clinical translation progresses, these platforms are expected to democratize precision immunotherapy by decoupling treatment efficacy from genetic prediction algorithms via direct incorporation of native tumor antigen ensembles and enabling real-time therapeutic adaptation to the evolving dialectic between immune surveillance and tumor immune evasion. This dual capacity positions nanovaccines as the first truly context-aware immunotherapy modality capable of addressing both interpatient heterogeneity and intratumoral temporal dynamics.317Spatiotemporal codelivery of antigens and adjuvantsTraditional personalized cancer vaccines have induced potent antitumor immune responses in preclinical and clinical studies; however, their efficacy remains limited, in part because of the antigen-adjuvant delivery mode.318 Current strategies predominantly employ binary formulations, administering tumor-derived antigens (neoantigens, TAAs, or peptide libraries) as isolated entities or physically admixed with immunostimulants such as TLR agonists, alum, or cytokines. This fragmented approach disregards the spatiotemporal precision required for optimal immune synapse formation, as evidenced by three critical problems: (1) discrete antigen delivery induces rapid extracellular protease degradation and off-target dispersion, resulting in low DC uptake efficiency, (2) isolated adjuvant administration triggers nonproductive inflammation through systemic cytokine storms rather than localized APC activation, and (3) physical mixtures exhibit pharmacodynamically discordant biodistribution profiles, with antigens accumulating in LNs before adjuvant arrival, thereby missing the critical window for coordinated MHC-II loading and CD40/CD86 costimulation.319 Emerging nanotechnology platforms may address these limitations through molecularly engineered codelivery systems that synchronize antigen-adjuvant delivery with cellular precision.320 By packaging patient-specific antigenic payloads with optimally dosed adjuvants (e.g., STING agonists or NLRP3 inflammasome activators) within pH-sensitive polymeric nanocapsules or lipid-based biphasic vesicles, these systems achieve temporal coordination of three essential immune-activation phases: lysosomal antigen processing, MHC-I/II epitope presentation, and costimulatory signal upregulation.321,322 This spatiotemporal orchestration mimics pathogenic invasion patterns, generating enhanced tumor-specific CD8+ T-cell activation compared to that induced by conventional vaccines.323 Nanotechnology-driven integration transcends mere physical coexistence; engineered ligand–receptor interfaces between antigenic epitopes and adjuvant molecules enable allosteric activation of APC intracellular signaling cascades, thus transforming passive antigen repositories into bioinspired architectures that recapitulate natural immune recognition dynamics.324The architectural sophistication of these nanocarriers lies in their ability to encode both antigenic specificity and immunomodulatory intelligence within a single particle. For instance, lipid-polymer hybrid NPs can be engineered to encapsulate patient-derived neoantigen peptides or tumor lysate-derived protein aggregates within their hydrophobic cores while concurrently embedding molecular adjuvants, such as CpG oligonucleotides (TLR9 agonists) or cyclic GMP-AMP synthase (cGAS)-STING pathway activators in their outer lipid layers.325,326 This spatial segregation prevents premature adjuvant leakage while ensuring synchronized release upon lysosomal degradation in APCs. Mesoporous silica NPs functionalized with pH-responsive gatekeepers can coload antigens and adjuvants within their porous structures, releasing payloads in a pH-dependent manner to coincide with DC maturation stages.327,328 Luo et al.329 recently developed a lipid nanogel vaccine that enhances endosomal membrane permeability in a nanogel core-dependent manner, effectively promoting cytosolic sensing of Poly I:C and cocoated neoantigens. Li et al.330 constructed a dual immunofunctional polymeric nanoplatform that encapsulates neoantigens (e.g., OVA) via electrostatic interactions. This nanocarrier simultaneously acts as a STING agonist and an immune adjuvant. It activates the STING pathway by inhibiting poly(18-crown-6-yl methacrylate)-mediated potassium ion perturbation cascades and endoplasmic reticulum stress, thereby promoting interferon-regulatory factor 3 phosphorylation. Additionally, it induces DC maturation through TLR4 activation via primary amine groups.330Numerous other biomaterials and inorganic materials allow excellent codelivery of neoantigens and adjuvants for personalized cancer treatment. For example, DC-derived exosomes loaded with neoantigens demonstrated superior synergistic antitumor efficacy over conventional liposomal formulations, attributed to their specific protein components.331 Qu et al.332 developed a biomimetic autophagosome-based nanovaccine by precisely amalgamating autophagosome-derived neoantigens and two adjuvants capable of targeting LNs. This redox-responsive nanovaccine facilitates cytosolic vaccine opening within APCs, thereby exposing adjuvants and antigens to stimulate a strong immune response.332 Recently, another study also reported a functional Ti2NX nanodot capable of binding to phosphatidylinositol-4-phosphate, a lipid marker present on the membrane of personalized autophagosomes, thereby preventing autophagosome-lysosome fusion and resulting in the formation of stable nanodot-coated autophagosomes within tumor cells. These nanodot-coated autophagosomes are subsequently released from cancer cells and trafficked to lymph nodes, where they promote the activation of tumor-specific T cells.333 A nanovaccine that combined a Bacille Calmette–Guérin bacterial cell wall skeleton-based nanoscale adjuvant with peptide neoantigens (M27 and M30) effectively targeted LNs, eliciting robust innate and tumor-specific immune responses.334 Iron oxide NPs have been shown to enhance OVA cross-presentation efficiency by inducing IFN-I production and activating the STING pathway, resulting in a 55-fold increase in antigen-specific CD8+ cytotoxic T-lymphocyte responses.335 Zhang et al.336 designed a high-efficiency tumor nanovaccine using a biomineralization-inspired one-step preparation method, integrating OVA, CpG adjuvant, and manganese NPs with dual carrier/adjuvant functions. Leveraging this platform’s strong loading capacity, a personalized nanovaccine was further developed using the supernatant of tumor abrasive fluid as personalized antigens. When combined with anti-PD-L1 therapy, the nanovaccine effectively suppressed postsurgical tumor recurrence and induced durable immune memory effects.336 Zhang et al.337 developed a tumor nanovaccine platform that integrates adjuvant functions into a personalized mRNA delivery vehicle using branched polyguanidine nanovaccines, which effectively stimulated DCs, promoted their maturation via the TLR4 and NLRP3 pathways, and triggered robust immune activity in vivo. Li et al.338 developed a fluoroalkane-modified cationic polymer for use in personalized mRNA cancer vaccines.Surface engineering strategies further enhance vaccine precision. Antigen peptides conjugated to NP surfaces via reducible disulfide bonds or enzyme-cleavable linkers ensure rapid exposure to DC surface receptors, while adjuvants embedded within the particle are released at a later point in time to amplify cross-presentation via endosomal TLRs or cytosolic sensors.339,340,341 “Dual-shell” nanovaccines represent a groundbreaking innovation. In this approach, an inner layer of poly(lactic-co-glycolic acid) encapsulates antigens alongside autophagy-inducing adjuvants, such as rapamycin, while an outer shell of tumor-cell membrane fragments decorated with CD47 “do not eat me” signal blockers delays phagocytic clearance, thus prolonging LN retention.342,343,344 Such nanovaccines not only increase antigen concentrations within APCs but also modulate intracellular trafficking pathways. For example, mannose-modified NPs coloaded with antigens and the STING agonist 5,6-dimethylxanthenone-4-acetic acid redirect cargo from lysosomal degradation to cytosolic pathways, boosting cross-presentation on MHC-I compared to that achieved by physical mixtures.345 These technologies ensure that antigens and adjuvants act in concert to ignite cascades of CD8+ T-cell priming, Th1 polarization, and memory cell formation.346,347,348 Cheng et al.277 designed a versatile outer membrane vesicle-based nanovaccine to elicit a specific antitumor immune response by presenting antigens on outer membrane vesicle surfaces through fusion with the ClyA protein, an OMV cargo protein from E. coli. They simplified the antigen display process by employing a plug-and-display system comprising tag/catcher protein pairs. The outer membrane vesicles decorated with different protein scavengers simultaneously display multiple distinct tumor antigens to elicit a synergistic antitumor immune response.277 Another study also corroborated this antigen display approach as a personalized vaccine strategy.349Hybrid membrane systems further augment vaccine/adjuvant codelivery through chimeric fusion of tumor membranes with APC derivatives or biomimetic membranes. For example, Chen et al. developed an autologous tumor/Escherichia coli hybrid nanovaccine for tumor-cell membrane delivery after surgery.17,350 Wang et al.351 developed a functional hybrid membrane nanovaccine by integrating ginseng-derived extracellular vesicle-like particles into autologous tumor membranes. The incorporation of ginseng-derived particles significantly enhanced DC phagocytosis of autologous tumor antigens while promoting DC maturation through TLR4-mediated signaling, ultimately activating tumor-specific CTLs to elicit potent antitumor immunity.351 Shi et al.352 constructed personalized liposomes with cancer cell membranes and the adjuvant R848 that showed immunostimulatory efficacy, provided time for identifying tumor antigens, and boosted the immune response.352Moreover, pretreatment of tumor-cell membranes represents a promising strategy to enhance the immunogenicity of tumor antigens. Recently, Li et al. developed a rapid and versatile method for constructing personalized nanovaccines using antigen-enriched tumor-cell membranes (AECM), leveraging the ability of interferon-γ to potently upregulate antigen presentation across a diverse array of cancer cell types. By coupling the resulting AECM with PC7A, a polymeric STING, they developed AECM@PC7A nanovaccines. Even at low doses, these nanovaccines elicited robust T-cell responses against multiple neoepitopes, leading to significant tumor regression and suppression of metastasis in several murine cancer models.353 Chen et al. reported that autologous tumor-cell membrane-based vaccines derived from tumors pretreated with liposomal doxorubicin enhance dendritic cell maturation and T-cell activation more effectively than free doxorubicin. This formulation demonstrated improved efficacy in preventing postsurgical recurrence and metastasis in a murine model.354 Similarly, Li et al. engineered personalized pyroptotic vesicles from autologous tumor cells, which are enriched with tumor antigens and exhibit inherent immunostimulatory properties. When encapsulated in a biocompatible hydrogel, these vesicles can be implanted into postresection tumor cavities to effectively inhibit tumor recurrence.355The superiority of codelivery systems over conventional antigen-adjuvant mixtures is rooted in their ability to transcend the “signal dilution” effect associated with traditional vaccines. Physical mixtures allow antigens and adjuvants to diffuse independently, with low colocalization in DCs, which undermines productive immune synapse formation.356,357 Nanovaccines address this inefficiency by enforcing a random antigen-to-adjuvant ratio within each personalized carrier, ensuring that every DC engulfing an NP receives both signals required for activation.358 Mechanistically, synchronized delivery prevents the “adjuvant paradox,”, i.e., early adjuvant exposure in the absence of antigen primes regulatory T cells instead of effectors by ensuring that TLR/nucleotide-binding oligomerization domain-like receptor activation coincides with antigen availability.359,360 Furthermore, nanocarriers protect labile adjuvants, such as mRNA or IL-15 superagonists, from extracellular nucleases and proteases, extending their half-life from minutes to days.361 Furthermore, codelivery minimizes systemic toxicity by restricting adjuvant activity to antigen-loaded DCs, avoiding cytokine storms triggered by free adjuvants.362 Crucially, this platform allows dynamic personalization, adjusting adjuvant classes (e.g., switching from TLR7 agonists for immunogenic tumors to STING agonists for “cold” tumors) while maintaining covalent antigen-adjuvant pairing.363 By transforming vaccines from crude mixtures into spatiotemporally controlled immunologic devices, codelivery nanotechnology redefines personalized oncology, offering a universal framework to amplify, rather than merely predict, the immune response.Multidimensional nanoplatforms for combinatorial immunotherapyCombinatorial immunotherapy, an important but hitherto unmet need for cancer treatment, is driven by the constraints of conventional combination therapies that depend on external therapeutics, such as radiotherapy, chemotherapy, or checkpoint inhibitors.364 Such combinatorial strategies seek to enhance antitumor immunity through the integration of antigen-specific vaccines as neoadjuvant or adjuvant therapies; however, their clinical effectiveness remains constrained by systemic toxicity, temporal inconsistencies, and spatial mismatches.365 Traditional personalized cancer vaccines, typically coadministered with chemotherapy or radiation, fail to synchronize the release kinetics of antigens, adjuvants, and complementary agents, resulting in suboptimal immune activation and collateral damage to healthy tissues.60,366 Emerging multidimensional nanovaccines address these challenges by consolidating patient-specific neoantigens, immunostimulatory adjuvants, and combinatorial therapeutics, including small-molecule inhibitors, radiosensitizers, and checkpoint-blocking antibodies, within a unified nanoscale delivery system.367 This structural integration facilitates spatiotemporally coordinated release, ensuring synchronized antigen presentation, adjuvant-induced DC maturation, and precise TME modulation.368 By coencapsulating multifunctional components, nanovaccines synergistically amplify ICD, dismantle immunosuppressive tumor networks, and proactively circumvent therapeutic resistance, a paradigm shift unachievable through temporally staggered administration of discrete therapeutic modalities.369,370The technological cornerstone of this paradigm lies in nanotechnology-enabled precision engineering for spatially organized integration of multifunctional components within architecturally optimized carriers.371 Multilayered lipid NPs exemplify this principle through stratified compartmentalization, encapsulating hydrophobic chemotherapeutic agents, such as paclitaxel, within their core matrix, embedding hydrophilic neoantigen peptides in intermediary lamellar structures, and surface-displaying both PD-1/PD-L1-inhibitory nanobodies and STING pathway activators.372,373 For example, the C/G-HL-Man nanovaccine integrates autologous tumor-cell membranes with dual immunostimulants (CpG and cGAMP), achieving targeted LN accumulation to enhance DC-mediated antigen cross-presentation and amplify antigen-specific CTL responses. Complemented by fenofibrate-mediated peroxisome proliferator-activated receptor-α activation, this strategy reprograms T-cell metabolism to sustain CTL effector functions within the immunosuppressive TME through optimized lipid utilization.374 This hierarchical architecture enables programmed payload release kinetics: initial chemotherapeutic-induced ICD liberates endogenous tumor antigens, which are captured by DCs primed through spatially coordinated adjuvant activation, while surface-tethered checkpoint inhibitors persistently block tumor-associated PD-L1.375,376 Another study developed an immunostimulatory nanovaccine combining manganese oxide (MnO2)-loaded polymeric NPs with hybrid membranes from MnO2-conditioned tumor cells and DCs. This nanovaccine enhanced the activation of DCs and tumor-specific T-cell responses compared to single-membrane formulations, which was achieved through the synergistic integration of immunogenic cellular debris, Mn2+-mediated STING activation, and membrane-bound T-cell costimulatory signals.377 Dendritic mesoporous silica NPs functionalized with tumor-penetrating peptides have been used to coencapsulate radiosensitizing gold NPs with antigen-encoding mRNA complexes and TGF-β signaling inhibitors.378,379 Radiation-triggered activation initiates cascading therapeutic effects: localized reactive oxygen species (ROS) generation disrupts tumor matrix integrity, released mRNA templates drive endogenous antigen production in APCs, and concurrent TGF-β pathway suppression counteracts regulatory T-cell immunosuppression.380,381 Other advancements include dual-checkpoint nanogel systems that encapsulate CTLA-4 inhibitors within thermoresponsive polymeric matrices while surface-conjugating OX40 costimulatory agonists. Intratumoral administration followed by mild hyperthermia triggers simultaneous CTLA-4 blockade-mediated T-cell disinhibition and OX40-driven clonal expansion, ensuring spatial and temporal convergence of antagonistic checkpoint suppression and agonistic costimulatory activation within identical T-cell populations.382,383 This coordinated signal integration effectively circumvents compensatory resistance mechanisms inherent to sequential or anatomically segregated administration of immunomodulatory agents.One promising strategy in personalized cancer immunotherapy involves versatile gel-based nanovaccine platforms. For example, Liu et al. developed an injectable nanoin-gel vaccine (NIGel-Vax) by encapsulating tumor-derived proteins and a PEI-based adjuvant in a dextran-PEG hydrogel. This system achieved a 92% tumor suppression rate in a 4T1 breast cancer model, demonstrating strong potential for personalized postoperative therapy.384 In another study, a dendritic cell-mimicking nanovaccine (nanoDC) was fabricated using dendritic nanoparticles coated with membranes from stimulated bone marrow-derived cells by autologous tumor cells and Escherichia coli. These nanoDCs efficiently homed to lymph nodes and activated robust T-cell responses.385 Yang et al. designed a combinatory approach using a temperature-sensitive hydrogel loaded first with cyclophosphamide and later with CpG and autologous tumor lysates. This sequential release system enhanced cytotoxic T-cell activity, reduced toxicity, and improved survival in CT26 tumor models.386 Additionally, a bioinspired nanofibrous peptide hydrogel vaccine was developed through the coassembly of personalized antigen peptides, enabling tunable antigen loading and promoting DC presentation and CD8⁺ T-cell activation.387In situ personalized nanovaccines synergistically integrate locoregional therapeutic modalities, including photothermal, photodynamic, and sonodynamic therapies, to reprogram tumor lesions into endogenous antigen reservoirs while orchestrating spatially controlled immunomodulation.296,388 For example, photoresponsive copper sulfide NPs exhibit near-infrared photothermal conversion capabilities to generate localized hyperthermia that induces immunogenic necrosis and TAA liberation.389 These nanostructures concomitantly liberate coencapsulated TLR7/8 agonists (e.g., resiquimod) and indoleamine 2,3-dioxygenase inhibitors into the peritumoral milieu, transforming ablation zones into immunologically active niches.390,391 Huang et al.390 created a tumor-cell membrane-camouflaged black phosphorus-gold nanovaccine enabling localized photothermal therapy and immune activation against metastatic breast tumors. Zhao et al.392 designed a biodegradable nanovaccine combining antigen-loaded MnO2 with amphiphilic γ-PGA/polylysine polymers that synergistically transport antigens to the DC cytosol while acting as intrinsic adjuvants. This system further utilizes near-infrared-triggered photothermal effects to induce tumor ICD and in situ antigen release, creating a closed-loop therapeutic strategy for personalized treatment. These systems operate as dual-purpose systems in which thermal or oxidative stress induces both tumor mass reduction and epitope diversification through stress-induced post-translational protein modifications, while integrated molecular adjuvants and gene-editing tools sustain antitumor immune surveillance.393 Recently, Qin et al.394 developed a nanovaccine consisting of a gold NP core covered with bacterial exosome components. The former affords an inducible hyperthermia effect, whereas the latter mobilizes diverse immune responses. Its multiple pattern-recognition receptors actively trigger immune responses, resulting in a broad spectrum of proinflammatory cytokine release and effector immune cell activation.394Sonodynamic therapy-enhanced platforms further advance this concept. Ultrasound-responsive titanium dioxide NPs allow for the generation of spatially confined ROS bursts to degrade extracellular matrix components, thereby liberating tumor-derived DNA fragments that activate cytosolic cGAS-STING surveillance mechanisms in tumor-infiltrating APCs.395,396 Recently, Wang et al.397 engineered an ultrasound-responsive nanovaccine by integrating the sonosensitizer Chenghai chlorin and immunoadjuvant R848 onto a sub5-nm dendrimeric scaffold. This platform capitalizes on the deep tissue penetration and spatiotemporal precision of ultrasound to noninvasively activate antitumor immunity in deep-seated malignancies. Under ultrasound irradiation, this nanovaccine orchestrates tumor antigen release while inducing phased TME remodeling from immunosuppressive (“cold”) to immune-active (“hot”) through R848-mediated immunostimulation and Chenghai chlorin-induced ROS generation, achieving simultaneous localized therapy and systemic immune amplification.397Collectively, these architectures establish a self-amplifying immunotherapeutic circuit in which therapy-induced antigen exposure is intrinsically coupled with TME-specific immune potentiators, circumventing conventional requirements for ex vivo antigen identification or synthetic neoantigen production. In situ antigen capture is another personalized nanovaccine strategy. A personalized nanochaperone has been designed for in situ TAA capture to improve cancer immunotherapy.398 Yu et al.399 developed maleimide-modified pluronic F127-chitosan NPs encapsulating Astragalus polysaccharide that can capture multifarious and immunogenic tumor antigens generated through cryoablation, specifically target LNs, and facilitate lysosomal escape to activate remote DCs.399The superiority of multidimensional nanoplatforms over conventional combinatorial strategies is evident across pharmacokinetic, pharmacodynamic, and clinical dimensions. Unlike traditional vaccines that require separate administration of antigens, adjuvants, and adjunct therapies, each with distinct biodistribution profiles,53,227 nanovaccines ensure that all components colocalize within the same tumor or lymphoid organs.400 Moreover, these platforms mitigate systemic toxicity: NP surface PEGylation or tumor-targeting ligands (e.g., folate, HER2 aptamers) minimize off-target accumulation, while controlled release kinetics reduce cytokine release syndrome risks.181 Beyond safety, nanoplatforms enable dynamic personalization; modular designs allow rapid substitution of antigens, adjuvants, or drugs based on real-time tumor sequencing or immune monitoring. Conceptually, this represents a shift from “static” combination therapies to adaptive, tumor-responsive systems—a leap toward precision immuno-oncology, in which vaccines evolve in tandem with the malignancy.401Systemic immune response: bridging innate–adaptive networksTraditional personalized cancer vaccines, while revolutionary in their capacity to prime adaptive immunity, struggle to effectively engage the innate immune system or establish durable immunological memory, which are critical shortcomings given the interdependent nature of innate and adaptive responses in eradicating malignancies.402 Systemic immune activation refers to the coordinated mobilization of both innate and adaptive immunity across anatomical compartments, characterized by sustained clonal expansion of tumor-specific T/B lymphocytes. Conventional approaches, such as peptide- or mRNA-based personalized vaccines, predominantly focus on delivering TSAs to DCs for MHC-mediated T-cell activation,38 neglecting the foundational roles of innate immune cells (macrophages, natural killer cells, and neutrophils) in initiating antigen-agnostic tumor surveillance, shaping the cytokine milieu, and sustaining memory T-cell populations.403 Without coordinated innate activation, adaptive responses often falter due to insufficient DC maturation, immunosuppressive myeloid-derived suppressor cell infiltration, or failure to recruit tissue-resident memory T cells.404 Personalized multifunctional nanovaccines address this systemic deficit by simultaneously delivering patient-specific antigens, innate-stimulating adjuvants, and immune memory-promoting cues. Through innovations, such as biomimetic membrane coatings, pathogen-mimetic nanostructures, and cargo-sequestered cytokine depots, these nanoplatforms promote innate–adaptive crosstalk, converting transient T-cell activation into robust, long-term antitumor immunity.The architectural ingenuity of these systems lies in their ability to co-opt innate immune pathways while programming adaptive memory. For instance, neutrophil membrane-coated NPs loaded with neoantigens and the STING agonist cGAMP exploit the innate homing capabilities of neutrophil membranes to target tumor-associated inflammatory sites.405 Upon reaching the TME, the NPs release cGAMP to activate STING in tumor-infiltrating DCs and macrophages, inducing IFN-α/β production for the cross-presentation of codelivered neoantigens to CD8+ T cells.405 Concurrently, the CD11b/CD18 integrins in the neutrophil membrane bind to ICAM-1 on endothelial cells, prolonging NP retention to sustain innate activation. To ensure prolonged immunological memory, some nanovaccines incorporate IL-7/IL-15 cytokine scaffolds within their cores, which slowly release these homeostatic cytokines postantigen clearance.406,407“Priming-boosting” nanovaccines that combine pathogen-like β-glucan shells (activating dectin-1 on macrophages) with inner layers of antigen-adjuvant complexes represent another breakthrough.408 Guo et al.409 developed a biomimetic nanovaccine consisting of poly(N-vinylcaprolactam) nanogels coloaded with MnO2, the sonosensitizer chlorin e6 (Ce6), and the STING agonist cGAMP and cloaked with immunogenic apoptotic cancer cell membranes. The membrane coating facilitates LN-targeted delivery and APC recognition, while Mn2+ and cGAMP synergistically activate the STING pathway to prime systemic antitumor immunity. Under ultrasound, the nanovaccine spatiotemporally releases Mn2+ and Ce6 to drive localized hydroxyl radical/singlet oxygen generation, inducing ICD through chemodynamic/sonodynamic therapy. Concurrently, tumor-released Mn2+ amplifies STING activation, coupling ICD-derived antigen exposure with innate immune stimulation. This self-reinforcing system achieves full-cycle immunomodulation by integrating direct tumor ablation, ICD-mediated antigen release, and dual APC/tumor-cell immune activation, effectively suppressing bilateral tumor progression via systemic and localized therapeutic crosstalk.409 The β-glucan shell triggers trained immunity, also known as innate immune memory, and is a persistent hyperresponsive functional state of innate immune cells in myeloid cells, a form of innate memory characterized by epigenetic reprogramming and metabolic shifts that amplify adaptive responses to subsequent antigen exposures.410,411Nanovaccines engineered with CD40L-mimetic aptamers or OX40L-conjugated surfaces directly ligate costimulatory receptors on DCs and T cells, bypassing the need for endogenous cytokine support.412,413 Liu et al.414 recently developed a nanosized metal-organic (copper-tetrahydroxybenzoquinone) framework codelivering an alkaline phosphatase-activated substrate and ERK5 inhibitor (XMD8-92) for in situ personalized vaccination. Tumor-enriched alkaline phosphatase in early endosomes triggers the framework to generate •O2– via type I photodynamic reactions, while concurrent Fenton-like catalysis converts O2 and H2O2 into •O2–/•OH. This ROS surge activates caspase-3-mediated pyroptosis via phospholipase C and induces cuproptosis, induced by excessive copper (Cu) accumulation within cells, through dihydrolipoamide S-acetyltransferase oligomerization. The liberated •OH releases XMD8-92 to block macrophage efferocytosis, converting apoptosis into immunogenic secondary necrosis. Synergistic pyroptosis, cuproptosis, and necrosis collectively reprogram immunosuppressive “cold” tumors into antigen-rich “hot” ones.414The above strategies ensure that innate immune activation is not merely a transient prologue to adaptive responses but an integrated, self-reinforcing circuit that sustains effector and memory T-cell populations. B-cell immune activation is considered crucial for adaptive immunity.25,415 Yan et al. engineered a spatiotemporally coordinated nanovaccine by covalently conjugating immunostimulatory CpG oligonucleotides and anti-CD40 antibodies onto triple-negative breast tumor-derived membrane vesicles. The construct achieves LN-targeted delivery through anti-CD40-mediated CD40 recognition, ensuring efficient uptake by APCs. Tumor antigens displayed on the vesicle surface engage B-cell receptors to initiate activation, while synergistic CpG–TLR9 and anti-CD40–CD40 interactions amplify costimulatory signaling, enhancing both antibody production and antigen presentation in B cells. The platform concurrently primes DC-dependent CD8+ T-cell responses and reprograms tumor-associated macrophages, orchestrating coordinated adaptive and innate antitumor immunity.416The distinguishing strength of innate–adaptive interface personalized nanovaccines lies in their capacity to resolve the suboptimal immune activation associated with conventional immunization approaches. While traditional antigen-specific formulations produce limited cytotoxic T-cell activation because of inadequate DC maturation and failure to remodel immunosuppressive tumor niches, these integrated nanoplatforms achieve coordinated multiscale immune regulation through three fundamental innovations.369 First, they unify antigen presentation with innate immune activation by codelivering danger signals that license APCs while recruiting naïve lymphocytes through chemotactic guidance. Second, their engineered architectures concurrently neutralize microenvironmental immunosuppression and reinforce T-cell effector functions, thereby preventing compensatory immune evasion mechanisms. Third, they implement sustained antigen exposure systems that surpass the transient immunological memory of conventional vaccines, as clinically evidenced by multiyear maintenance of tumor-specific immune surveillance. This tripartite mechanism transforms cancer vaccination from a unidirectional antigen challenge into a dynamic immune-engineering process that not only initiates antitumor responses but also perpetually adapts them through real-time integration of tumor-derived signals.34 By creating a self-sustaining circuit of innate sensing, adaptive targeting, and microenvironmental reprogramming, these systems fundamentally redefine therapeutic vaccination as an evolving biological interface rather than a static immunological intervention.417Clinical trials of personalized cancer vaccines across cancer typesIdentification of personalized tumor antigens in the clinicThe core of personalized cancer vaccines is to identify and apply patient-specific tumor antigens to induce potent and targeted immune responses that depend on neoantigens, tumor-specific peptides originating from somatic mutations that are not expressed in normal tissues. The comprehensive identification and validation of these neoantigens entail an integrated multistep workflow incorporating genomics, bioinformatics, and immunology.51 The process typically commences with the detection of somatic mutations via high-throughput sequencing methodologies. Whole-exome sequencing (WES) and RNA sequencing (RNA-seq) comparing tumor and matched normal samples facilitate the identification of genetic alterations such as single-nucleotide variants (SNVs), insertions and deletions (indels), gene fusions, and alternative splicing events.76,418,419 RNA-seq plays an especially critical role in verifying the expression of mutant alleles and unveiling aberrant splicing patterns or microbial contributions that might expand the immunopeptidome.420 Furthermore, long-read sequencing technologies, including nanopore-based platforms, significantly enhance the accuracy of full-length transcriptome analyses, thereby improving the detection of neoantigens derived from frameshift mutations and noncanonical isoforms.59 Subsequent to mutation identification, computational prediction serves to prioritize candidate neoantigens. A prerequisite step is HLA typing, which determines the patient’s specific HLA-I (HLA-A, -B, -C) and HLA-II (HLA-DR, -DQ, -DP) alleles essential for peptide presentation. Tools such as Optitype and Polysolver are commonly employed for HLA-I genotyping, whereas arcasHLA and seq2HLA are utilized for HLA-II alleles.64 Following HLA genotyping, mutation-calling pipelines filter somatic variants based on criteria including variant allele frequency, gene expression level, and predicted impact on protein function. A pivotal aspect of this workflow involves predicting HLA binding and antigen presentation. Machine learning-based algorithms such as NetMHCpan and MHCflurry are widely used to estimate peptide-MHC-I binding affinity, leveraging mass spectrometry-derived immunopeptidome datasets. For MHC-II molecules, which display greater peptide-length flexibility and allelic diversity, tools such as MARIA and MixMHC2pred incorporate deep learning strategies to enhance predictive accuracy.421 Nevertheless, binding affinity represents only one factor; other elements, including proteasomal cleavage, TAP transport efficiency, and peptide-MHC complex stability, collectively shape antigen presentation. Emerging technologies such as ESCAPE-seq offer promising avenues to overcome these limitations by enabling high-throughput parallel screening of peptide–HLA interactions. This DNA sequencing-based platform can simultaneously evaluate over 75,000 peptide–HLA combinations, encompassing diverse alleles, including undercharacterized ones such as HLA-C, and demonstrates high sensitivity in detecting low-abundance neoantigens. For example, ESCAPE-seq has successfully identified shared neoantigens from driver mutations such as EGFR T790M presented across various HLA alleles, suggesting potential applicability across broader patient populations.422 The final step involves experimental validation of immunogenicity. Candidate neoantigens are typically assessed using T-cell functional assays such as IFN-γ ELISpot, MHC multimer staining for antigen-specific T-cell detection, or TCR sequencing. It is important to note, however, that only a subset of in silico-predicted neoantigens successfully elicit immune responses, owing to mechanisms such as T-cell tolerance or suboptimal TCR recognition.423 Mass spectrometry-based immunopeptidomics serves as a gold-standard method for direct verification of HLA-bound peptides, enabling the identification of neoantigens that may be overlooked by purely genomic approaches, including those resulting from post-translational modifications. Despite persistent challenges such as tumor heterogeneity and inconsistencies in prediction accuracy, the integration of multiomics data with advanced machine learning continues to accelerate the field of neoantigen discovery. Clinical milestones, including mRNA-based personalized vaccines such as mRNA-4157, underscore the feasibility of targeting neoantigens to provoke durable T-cell-mediated antitumor immunity and improve clinical outcomes.424 In this section, we review the latest clinical trials of personalized cancer vaccines using data from ClinicalTrials.gov and relevant publications retrieved from PubMed with the keyword “personalized cancer vaccine” published within the last three years (2023–2025). Earlier clinical trials have been extensively covered in previous reviews.2,21Clinical trials for monotherapy of personalized cancer vaccinesThe period from 2023 to 2025 has marked significant clinical progress in the development of personalized cancer vaccines, solidifying this modality as a promising therapeutic strategy across diverse cancer types. Extended follow-up data from studies of personalized mRNA-4157 (V940) in combination with pembrolizumab continue to demonstrate sustained clinical benefit, with three-year recurrence-free survival rates remaining superior to those achieved with pembrolizumab monotherapy.11,12,425 These consistent efficacy outcomes have prompted the global expansion of Phase 3 trials, with regulatory submissions expected by 2027. Notably, groundbreaking advances in pancreatic cancer vaccine research have emerged during this period. A personalized mRNA vaccine developed by BioNTech exhibited remarkable efficacy in patients with pancreatic ductal adenocarcinoma. Vaccine-induced immune responses persisted for nearly four years in some individuals, correlating with a reduced risk of cancer recurrence at the three-year follow-up compared to nonresponders.11 Among these responders, the average estimated lifespan of CD8+ T-cell clones induced by the cevumeran vaccine reached 7.7 years, with a range from 1.5 to approximately 100 years. Approximately 20% of these clones exhibited latent lifespans extending over several decades, potentially exceeding the host’s own survival time.13 This breakthrough is particularly meaningful for a malignancy as challenging as pancreatic cancer, where five-year survival rates historically remain at approximately 12%, signaling a paradigm shift in vaccine applications even for cancers traditionally resistant to immunotherapy. Similar encouraging results have been reported in advanced renal cell carcinoma. With a median postoperative follow-up of 40.2 months and a median of 34.7 months from the initiation of personalized neoantigen peptide vaccination, none of the nine evaluated patients experienced disease recurrence, achieving a 100% recurrence-free rate. The personalized cancer vaccine proved highly immunogenic across all patients, each of whom developed T-cell responses against personalized cancer antigens. Importantly, five out of the nine patients mounted immune responses against all four peptide libraries included in the vaccine.426In addition to the reported successes in clinical trials, we have summarized the latest trials of personalized cancer vaccines from 2023 to 2025 using clinicaltrials.gov. The current landscape is defined by a diverse and rapidly growing portfolio of clinical investigations encompassing a wide array of vaccine platforms (Table 2). DNA, mRNA, peptide, DC, and tumor-cell-based vaccines are all being actively investigated across a range of malignancies, including solid tumors, brain cancers, pancreatic cancer, acute myeloid leukemia, triple-negative breast cancer, and ovarian carcinomas. Most trials are in early-phase development (phase 1 or phase 1/2), with primary endpoints centered on establishing safety, tolerability, and recommended dosing—commonly measured through maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and adverse events (AEs). Notably, several mRNA-based vaccines, such as PGV002 and XP-005, are under evaluation in larger cohorts (e.g., N = 36–60) for conditions such as solid tumors and AML, underscoring growing translational interest in RNA platforms. Peptide vaccines, for instance, neoantigen polypeptide vaccines in ovarian cancer, increasingly incorporate efficacy endpoints, including the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), reflecting the progression of certain candidates into later-stage testing. Dendritic cell vaccines and tumor-cell-based formulations continue to be optimized, particularly in immunologically challenging contexts such as glioma and triple-negative breast cancer. Together, these efforts highlight a concerted shift toward tailored immunotherapies, with a focus on neoantigen-directed approaches and combination strategies designed to address unmet needs in oncology.Table 2 Clinical trials for monotherapy of personalized cancer vaccines from 2023 until now via clinicaltrials.gov and PubMedFull size tableClinical trials for combinatorial therapy of personalized cancer vaccinesThe development of personalized cancer vaccines has increasingly focused on combinatorial strategies, reflecting the recognition that monotherapies often fail to adequately counteract the immunosuppressive tumor microenvironment.364 Combining personalized vaccines with other immunomodulatory agents, such as immune checkpoint inhibitors (ICIs), radiotherapy, or adoptive cell therapies, aims to synergistically enhance antitumor immunity by improving antigen presentation, reversing T-cell exhaustion, and eliciting broader, more sustained immune responses. This strategy is designed to reignite the cancer-immunity cycle, promoting enhanced T-cell infiltration, recognition, and cytotoxicity against tumor cells.427Personalized cancer vaccines with immune checkpoint inhibitorsRecent clinical trials highlight a sharp increase in exploration of such combinations, as evidenced by a growing number of studies registered over the past year (Table 3). The most prominent strategy involves combining personalized vaccines, particularly mRNA-based formulations such as mRNA-4157 and Autogene Cevumeran, with PD-1/PD-L1 inhibitors such as pembrolizumab, nivolumab, and atezolizumab. These trials cover a broad spectrum of cancers, with notable emphasis on malignancies historically resistant to immunotherapy, including pancreatic cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC). For example, several phase 3 trials are investigating mRNA-4157 combined with pembrolizumab in melanoma, NSCLC, and cutaneous squamous cell carcinoma, using recurrence-free survival (RFS) and disease-free survival (DFS) as primary endpoints. Large patient cohorts, often numbering in the hundreds, demonstrate a focused effort to establish efficacy in advanced disease settings. Similarly, early-phase trials are assessing comparable combinations in urothelial carcinoma, triple-negative breast cancer, hepatocellular carcinoma, and acute myeloid leukemia, frequently incorporating endpoints such as safety (DLTs, AEs), immunogenicity (T-cell responses), and additional efficacy measures including ORR and disease control rate (DCR).Table 3 Clinical trials for combinatorial therapy of personalized cancer vaccines from 2023 until now via clinicaltrial.govFull size tablePersonalized cancer vaccines with other cancer therapeuticsBeyond immune checkpoint inhibitors, other innovative combinations are emerging. For instance, vaccine-radiotherapy synergies are being explored in NSCLC using neoantigen-based dendritic cell or peptide vaccines, with the goal of enhancing antigen release and presentation while capitalizing on the immunostimulatory effects of radiation. Another promising approach combines personalized DC vaccines with CAR-T therapy in B-cell acute lymphoblastic leukemia to improve T-cell engagement and persistence. Additionally, combinations with targeted agents, such as lenvatinib together with nivolumab and a DC vaccine in gastrointestinal cancers, exemplify strategies aiming to simultaneously disrupt multiple pathways within the tumor microenvironment.Overall, the clinical landscape for combination therapy with personalized cancer vaccines is characterized by a strategic emphasis on immune priming and modulation. Vaccines are utilized to initiate tumor-specific immune responses, while combination agents are intended to overcome inhibitory signals and amplify effector mechanisms. Although most trials remain in early or mid-phase development, the expanding variety of cancer types and combination partners reflects a maturing field increasingly aimed at overcoming resistance mechanisms and achieving durable clinical benefits through multimodal immunotherapy.Potential of personalized cancer vaccines in postoperative recurrence and metastasis preventionDespite significant advances in surgical techniques and adjuvant therapies, postoperative recurrence and metastasis continue to be major contributors to cancer-related mortality.428 Even following complete resection, minimal residual disease and disseminated tumor cells frequently persist, evading detection and ultimately leading to disease relapse.429 This persistent clinical challenge highlights the critical need for preventive strategies capable of selectively targeting residual tumor cells while establishing durable immunological memory to prevent recurrence.430 Personalized cancer vaccines have arisen as a promising therapeutic modality to meet this demand, harnessing patient-specific tumor antigens to initiate a potent and targeted immune response designed to eliminate residual cancer cells after primary surgery.369The postoperative period represents a unique therapeutic window for intervention. Resected tumor tissue provides a critical source for antigen identification, facilitating the design of vaccines that mirror the individual mutational landscape of each patient’s cancer.431 Through comprehensive sequencing of the primary tumor, neoantigens derived from somatic mutations and exclusively expressed by cancer cells can be reliably predicted and selected for vaccine development.63 This strategy reduces the risk of autoimmunity and focuses immune reactivity on genuinely tumor-specific antigens. Postoperative vaccination takes advantage of the reduced tumor burden and a potentially less immunosuppressive microenvironment, enabling the primed immune system to mount a more robust response against disseminated microtumors and dormant metastatic niches.432 Personalized vaccines, especially those utilizing mRNA or peptide platforms, are engineered to activate both CD8+ and CD4+ T cells, promoting a polyclonal T-cell response capable of recognizing and eliminating heterogeneous tumor populations. Such broad immunoreactivity is essential to mitigate immune escape and clonal expansion of antigen-loss variants.1 Moreover, effective vaccination induces persistent memory T cells, enabling long-term immunosurveillance that can prevent recurrence years after initial therapy. Early-phase clinical trials have yielded encouraging results in this context. For instance, in high-risk melanoma patients, postsurgical administration of personalized mRNA vaccines correlated with prolonged recurrence-free survival and expanded circulation of tumor-specific T-cell clones.11,12,425 Comparable outcomes have been reported in pancreatic cancer, glioblastoma, and renal cell carcinoma, where vaccine-induced immune responses were associated with decreased recurrence rates and delayed metastatic progression11,13. Similarly, in a large cohort of 79 patients with metastatic recurrent breast cancer, a personalized neoantigen peptide vaccine elicited broad immunogenicity and clinical efficacy. Most vaccinated patients exhibited enhanced CTL activity and/or IgG responses, with three complete responses and six partial responses observed.433 These results underscore the capability of neoantigen vaccines to provoke robust and subtype-specific immunity, even in advanced, treatment-resistant disease settings.Notably, combining personalized vaccines with other immunotherapies, such as ICIs, may further potentiate their efficacy by counteracting residual immunosuppression and prolonging T-cell effector function.369 Such combinatorial approaches are increasingly being investigated in the adjuvant setting, with the objective of achieving synergistic and sustained protection against recurrence. In summary, personalized cancer vaccines constitute a biologically rational and clinically viable strategy for the postoperative prevention of recurrence and metastasis. By exploiting the distinct antigenic fingerprint of each patient’s tumor, these vaccines provide a highly specific and adaptable means to eradicate minimal residual disease and establish long-term protective immunity.Clinical translation and future perspectives: advancing personalized cancer vaccines into clinical practiceClinical translation challengesThe clinical translation of personalized cancer vaccines from investigational concepts to widely accessible therapies remains fraught with substantial challenges, primarily centered around manufacturing complexity, ambiguous regulatory frameworks, high financial burdens, and protracted production timelines. In contrast to conventional “off-the-shelf” therapeutics, personalized vaccines require customization based on the mutational landscape of each patient’s tumor, necessitating a multistep workflow that encompasses tumor sequencing, neoantigen prediction, vaccine formulation, and rigorous quality control, each stage demanding stringent standardization and validation.47 This intricate manufacturing process introduces significant logistical obstacles, frequently requiring decentralized, specialized facilities operating under GMP conditions to manage patient-specific biological materials.23 Furthermore, the current production timeline, often extending over several months, risks delaying treatment initiation, potentially diminishing therapeutic efficacy, especially in aggressively progressing cancers. Compressing the biopsy-to-vaccination (“needle-to-needle”) interval is also paramount to feasibly incorporate individualized vaccines into established treatment protocols. For instance, patients with pancreatic cancer who undergo tumor resection should ideally commence adjuvant chemotherapy within 12 weeks post-surgery to attain survival benefits.434 Thus, to administer vaccines before standard adjuvant therapies, immunization would need to occur within this critical window.Regulatory bodies, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), are continually adapting to the unique challenges posed by personalized immunotherapies. There is an urgent need for clearly defined and harmonized regulatory guidelines that accommodate the dynamic and bespoke nature of these products—particularly concerning the evaluation of potency, purity, and consistency across individually tailored vaccines. Additionally, the substantial expenses linked to personalized development and production raise concerns regarding economic viability and equitable access, potentially restricting patient eligibility and widespread clinical integration. The high cost of personalized neoantigen vaccines, which can currently exceed US$100,000 per patient for highly customized formulations, presents a major barrier to large-scale implementation.435 Recent advances in tumor-cell membrane-based personalized cancer vaccines offer a promising strategy to address the high costs and complexity associated with traditional neoantigen-based vaccines.89 Tumor-cell membrane-based nanovaccines derived from the patient’s own tumor-cell membrane can bypass the need for neoantigen identification and synthesis. Instead, tumor-cell membranes isolated from surgically resected or biopsied tumor tissues are directly integrated with immune adjuvants into nanocarriers, forming a biomimetic vaccine. This approach not only preserves the entire spectrum of tumor antigens, including known and otherwise unpredictable membrane antigens, enhancing the breadth of immune activation, but also substantially reduces development time and production costs.17 Further optimization of full membrane protein extraction, establishment of alternative tumor-cell sources (such as patient organoids for small tumors), and the adoption of scalable nanomanufacturing technologies such as microfluidics may facilitate large-scale production, thus lowering costs and accelerating clinical translation.436Notably, despite a growing number of early-phase trials demonstrating robust immunological activity and clinical benefits, only one personalized cancer vaccine, sipuleucel-T for prostate cancer, has attained regulatory approval by the FDA thus far. This discrepancy underscores the significant translational gap between promising preclinical or early clinical results and established therapeutic applicability.437 Future advancements will hinge on the development of automated and scalable manufacturing technologies, the refinement of adaptive regulatory pathways for platform-based personalized products, and validation through large-scale, randomized clinical trials across diverse cancer types and disease stages.438Integrating AI into personalized cancer vaccine developmentThe integration of AI into the development of personalized cancer vaccines has ushered in a paradigm shift in neoantigen discovery and vaccine design. Early exemplars such as IBM’s Watson Oncology illustrate how AI can leverage large-scale data repositories to generate tailored therapeutic recommendations, highlighting its potential in personalized oncology.439 In the realm of cancer immunology, AI and machine learning (ML) are driving substantial progress in epitope prediction, a fundamental aspect of effective vaccine development. For instance, DiscoTope-2.0 facilitates accurate B-cell epitope identification by calculating residue-specific epitope propensity through analyses of local structural characteristics, including side-chain orientation and solvent accessibility.440 Building on this foundation, DiscoTope-3.0 employs positive-unlabeled learning and inverse folding-based structural representations to achieve robust epitope predictions from both experimental and computationally modeled antigens, thereby diminishing reliance on experimental structures and expanding the scope of targetable antigens.441 Beyond structural prediction, ML techniques are being harnessed to translate somatic mutations into therapeutically actionable neoantigens, enhancing the selection of immunogenic targets with high clinical relevance.442,443 Additional computational strategies, including hybrid genetic algorithms coupled with support vector machines (SVMs), have further elevated predictive accuracy in epitope mapping.444 Tools such as PREDIVAC exceed conventional methodologies in predicting CD4+ T-cell epitopes and HLA class II peptide binding, thereby improving candidate prioritization.445 The synergy among computational analytics, high-throughput genomics, and machine learning offers considerable potential to streamline the identification of optimal therapeutic targets and predictive biomarkers, which is crucial for advancing personalized cancer vaccines.In the context of mRNA-LNP cancer vaccines, AI-driven platforms are also demonstrating important utility.446 The recently developed COMET by Chan et al., a transformer-based deep learning model trained on the extensive LANCE dataset, enables end-to-end prediction of LNP efficacy by integrating multicomponent and multimodal features. This capability supports the rational design of high-performing LNPs tailored for RNA therapeutics across diverse formulations and conditions.447 Other computational tools, such as POLYVIEW-3D,448 PyMOL,449 and COMSOL,450 along with specialized platforms such as NANOdesign, facilitate the rational design and optimization of LNPs for mRNA vaccine delivery. These systems support both de novo engineered nanostructures and those assembled through natural processes reliant on intermolecular forces, enabling spontaneous organization into functional nanoarchitectures. They provide advanced functionalities for precise modulation of lipid composition and stoichiometry, key parameters for achieving high mRNA encapsulation efficiency, structural stability, and desired biodistribution. Through systematic optimization of LNP formulations, these tools accelerate the development of effective and stable mRNA vaccine carriers, promoting their clinical translation.Advanced material innovationsThe integration of advanced nanomaterials and nanotechnology has fundamentally transformed personalized cancer vaccine development, providing innovative material-driven solutions to longstanding biological and technical limitations for clinical translation.451,452 State-of-the-art nanovaccines combining materials engineering and immunological principles are emerging via three critical advancements in nanobiointerfaces: the creation of architecturally sophisticated nanocarriers, the implementation of adaptive manufacturing strategies, and the engineering of precision theragnostic systems. This material-centric approach systematically addresses key challenges, such as tumor antigenic diversity, immunosuppressive niche modulation, and sustained immunogenicity, while pioneering novel functionalities, such as smart immune feedback systems and self-regulated therapeutic response mechanisms.55,371,453,454Advanced personalized nanovaccines combining biomimetic nanostructures with immunologically active interfaces embody a material science breakthrough in theragnostic integration.313 Central to this innovation is an engineered nanoarchitecture composed of size-optimized (50–200 nm) carrier matrices, including lipid-polymer hybrids, inorganic‒organic composites, and supramolecular assemblies, designed with surface topology and charge characteristics to optimize lymphatic trafficking and cellular uptake dynamics.34 Material surface engineering enables precise conjugation of patient-specific tumor antigens ranging from membrane-derived proteolipid complexes to genome-edited exosomes, preserving native tumor antigenic signatures, including post-translational modifications and lipid-carbohydrate conjugates.455 This material-based antigen preservation strategy overcomes the limitations of synthetic peptide vaccines by maintaining three-dimensional epitope conformations and heterogeneous tumor antigen profiles essential for multiantigenic immune activation.456The surface architecture of nanocarriers can be engineered through advanced functionalization techniques, incorporating immunoactive molecular architectures, such as DC-targeting antibody interfaces (e.g., CD205-specific recognition motifs), pathogen-mimetic surface topologies (TLR-activating polymeric patterns), and immune checkpoint-modulating nanocomponents (PD-1 inhibitory nanobodies).457,458,459 Such multifunctional surface engineering synergistically enhances cellular recognition, innate immune activation, and adaptive immune potentiation.460 Material core-shell engineering further enables the integration of multimodal adjuvant systems within stimuli-responsive matrices, incorporating STING-activating molecular complexes, metabolic interference agents, and epigenetic NP modification, all precisely encapsulated through pH/enzyme-cleavable chemical bonding or phase-segregated nanocompartmentalization.461,462 These smart material designs allow for the spatiotemporal control of drug release, with rapid adjuvant activation in early endosomal compartments and sustained antigen presentation through lysosomal degradation-resistant material formulations.369,463,464Material-driven nanovaccine development requires synergistic integration of nanostructured biomaterials with clinical manufacturing platforms.465,466,467 Surface functionalization begins with patient-derived antigen sources processed through microfluidic-based membrane purification systems, in which tumor-cell membranes are reconstituted with bacterial vesicle components via lipid bilayer fusion techniques, creating hybrid bionanomaterials that combine antigenic and adjuvant properties.468,469 Material optimization employs machine learning-enhanced materials informatics to correlate NP composition with patient-specific immune parameters, analyzing structure–property relationships between HLA-binding nanomaterials and immune cell activation profiles.470,471 Advanced manufacturing integrates bioorthogonal conjugation chemistry with high-throughput NP screening platforms, enabling rapid prototyping of lipid-polymer hybrids, inorganic‒organic core-shell structures, and biomimetic protein corona-engineered systems tailored for lymphatic targeting and immune evasion.472,473 Throughout this process, material characterization techniques, including cryo-electron tomography, surface plasmon resonance mapping, and in situ X-ray scattering, provide critical insights into nanostructure–immune functional relationships.451,474The evolution of nanomanufacturing strategies for personalized cancer vaccines centers on precision materials engineering, employing hierarchical self-assembly methodologies to construct antigen-adjuvant architectures that allow molecular-level control.319,475 Core-shell nanostructures are fabricated through modular material synthesis, where antigen-encapsulated cores and adjuvant-functionalized outer layers are independently engineered before integration via microfluidic hydrodynamic focusing, a process that enables nanoscale control over component stoichiometry and interfacial interactions,476,477 while ensuring pharmaceutical-grade reproducibility. Surface engineering exploits bioorthogonal click chemistry and nucleic acid-guided spatial patterning to create immune-active nanoplatforms with geometrically organized targeting ligands and checkpoint-modulating interfaces, optimizing receptor binding kinetics through surface topology design.478,479 To address tumor diversity, material innovation has led to multiplexed vaccine systems combining distinct NP subpopulations with programmed functional hierarchies: base NPs consisting of pH-stable material matrices deliver conserved TAAs, whereas secondary stimuli-responsive particles employ tumor protease-cleavable covalent bonds or supramolecular assemblies to sequentially release patient-specific neoantigens, achieving dynamic antigen presentation that mirrors tumor evolution.480,481,482Material-based therapeutic integration is realized through multifunctional hybrid nanosystems combining vaccine components with complementary treatment modalities.483 Engineered nanocomposites coencapsulating neoantigens and viral payloads utilize phase-separated material compartments to coordinate ICD induction and antigen release kinetics.484,485 Metabolic nanoregulators address TME challenges through enzyme-embedded catalytic materials, such as lactate oxidase-integrated metal-organic frameworks or catalase-functionalized polymer matrices, which chemically remodel immunosuppressive niches while generating oxygen via material-mediated redox reactions.486,487 For sustained immune memory, advanced biomaterials employ cytokine-conjugated hydrogel networks with tunable viscoelastic properties, creating lymphoid tissue-localized depots that maintain controlled cytokine elution through polymer degradation-engineered release profiles.488,489,490Safety concernsThe safety profile of personalized cancer vaccines demands rigorous evaluation, particularly regarding antigen selection and delivery system design. A fundamental concern for neoantigen-based approaches is the potential for off-target T-cell reactivity due to imperfect epitope prediction, which could precipitate severe autoimmune diseases.23 Conversely, vaccines employing engineered autologous tumor-cell membranes as antigen sources incorporate a complex repertoire of proteins, encompassing both nontumor-associated self-antigens and suboptimally presented tumor-associated antigens. This heterogeneity raises the possibility of inducing T-cell exhaustion or aberrant systemic inflammatory responses, such as cytokine release syndromes, mirroring limitations previously encountered with whole-tumor lysate vaccines.79 Further complicating the safety landscape, the in vivo persistence and degradation kinetics of polymeric nanocarriers require critical assessment; their dissolution not only modulates antigen release but also dictates systemic exposure to carrier components and metabolites, potentially eliciting unintended inflammatory or cytotoxic effects.491 Additionally, the autologous origin of membrane coatings, although advantageous for HLA compatibility, introduces profound scalability challenges within a GMP-compliant manufacturing paradigm, where ensuring consistent quality and safety across individualized batches presents a formidable obstacle.492Next-generation clinical developmentThe future development of personalized nanovaccines hinges on a synergistic strategy that integrates innovative material design, clinically relevant validation, and regulatory-aligned manufacturing.25 From a material perspective, next-generation nanovaccines should adopt modular platforms capable of codelivering antigens, adjuvants, and stimuli-responsive components to enhance immunogenicity and spatiotemporal control.30 Lipid-based (e.g., LNPs) or inorganic carriers (e.g., silica nanoparticles) can encapsulate mRNA or protein antigens while incorporating pathogen-associated molecular patterns to mimic natural infection and potentiate immune activation.493 Surface modification with targeting moieties such as DC-specific antibodies or mannose further promotes lymph node accumulation and antigen-presenting cell uptake.287 Biomimetic approaches, including cell membrane-coated nanoparticles or hybrid bacterial-tumor vesicles, capitalize on natural membrane compositions to present personalized neoantigens and evade host immune clearance. To improve in vivo delivery, nanocarrier mechanical properties, such as deformability, should be optimized through tunable polymeric or lipid-based systems.315From a clinical-translational standpoint, preclinical studies should prioritize human-relevant immune biomarkers and profiling techniques to better predict safety and efficacy.494,495 Efforts to incorporate animal-free models, such as immune organoids, microfluidic human-on-a-chip systems, and AI-driven simulations, will not only reduce ethical concerns but also improve clinical predictability and accelerate nanovaccine optimization. Furthermore, scalable and GMP-compliant manufacturing processes must ensure batch-to-batch consistency, formulation stability, and purity.496 Early-phase clinical trials would benefit from adaptive designs that efficiently evaluate immune responses and material-related toxicities, particularly for novel ionizable lipids or biodegradable polymers.497On the regulatory front, a problem-driven design philosophy is essential to reduce complexity and facilitate safety assessment of multifunctional nanomaterials. Modular platforms, exemplified by LNP systems with swappable antigenic cargo, enable diagonal translation across cancer types and leverage prior approval data for accelerated pathways.498 Regulatory agencies require a comprehensive characterization of critical quality attributes, including particle size, surface charge, degradation profile, and long-term biodistribution.499 Additional considerations, such as genomic privacy in neoantigen selection and cost-effectiveness analyses, are equally vital for successful clinical adoption and commercialization.500Concluding remarksThe advent of AI and nanotechnology-driven personalized cancer vaccines has redefined cancer immunotherapeutic boundaries through material innovation along with immunological precision to address the longstanding challenges of tumor heterogeneity, immunosuppression, and transient therapeutic efficacy. By leveraging advanced nanoplatforms, researchers have redefined the paradigms of antigen delivery, immune activation, and TME modulation, enabling spatiotemporally controlled codelivery of TSAs and immunomodulators. These engineered systems, ranging from biomimetic membrane-coated carriers to stimuli-responsive hybrid architectures, overcome the limitations of conventional vaccines by enhancing lymphatic trafficking, DC targeting, and antigen cross-presentation while preserving native antigenic diversity. The integration of AI for dynamic antigen selection and closed-loop biosensing technologies will further enhance therapeutic precision, allowing vaccines to adapt in real time to evolving tumor-immune dynamics.Despite promising clinical outcomes recently, fundamental scientific questions remain regarding personalized cancer vaccines. A central assumption has been that incorporating a larger number of neoantigens from a patient’s tumor into a vaccine would enhance the breadth and potency of antitumor immunity. However, emerging evidence suggests that due to mechanisms of immunodominance, most patients develop measurable T-cell responses against only a small subset of vaccinated neoantigens.11,501 This raises critical questions about whether increasing antigen quantity truly improves immune efficacy or merely amplifies off-target effects. Additionally, the rules governing antigen immunogenicity, such as HLA-binding affinity, TCR recognition thresholds, and antigen-processing efficiency, are still not fully deciphered. Future research must prioritize understanding the determinants of immunodominance and develop predictive models to select the most immunogenic neoantigens, potentially through integrated multiomics and machine learning approaches.46 Furthermore, the biological barriers within the TME, such as T-cell exhaustion, metabolic constraints, and immunosuppressive cells, can limit vaccine-induced responses.502 There is also insufficient evidence regarding the durability of immune memory elicited by personalized neoantigen vaccines and their ability to prevent long-term recurrence. Further research should focus on elucidating mechanisms that sustain effector T-cell function and memory formation, possibly through rational adjuvant design or synergistic combination with immunomodulators.From a clinical perspective, one key issue is identifying the optimal balance between personalized neoantigen vaccines and off-the-shelf, shared neoantigen platforms. While personalized vaccines offer high specificity, they involve complex logistics and extended production timelines. In contrast, off-the-shelf vaccines benefit from rapid deployment but may cover a narrower patient population.503,504 Hybrid strategies that combine both approaches represent a promising yet underexplored avenue. Another critical question is whether neoantigen vaccines will function best as monotherapies or require combination with other treatments, such as ICIs, chemotherapy, or radiation, to overcome resistance mechanisms and expand therapeutic efficacy. Clinical trials should also clarify whether these vaccines are effective only in minimal residual disease settings or can also induce regression in established metastases. Moreover, not all tumor types may be equally amenable to vaccination; factors such as tumor mutational burden, antigen presentation capacity, and immune infiltration levels will likely influence outcomes.46Translating neoantigen vaccines into routine clinical use demands scalable manufacturing processes, improved biocompatibility, and standardized immunomonitoring protocols. Challenges such as antigen-loss variants, interpatient heterogeneity, and inadequate immune memory formation underscore the need for smarter vaccine platforms, possibly incorporating nanomaterials, that enhance antigen delivery and promote innate immune activation.294,316,505 Future success will depend on collaborative, interdisciplinary efforts integrating immunology, bioinformatics, material science, and clinical oncology. By developing modular and adaptive vaccine systems capable of real-time immune feedback, the field may eventually shift from reactive treatment to proactive, precision immunoprevention. 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Immunother. 69, 1375–1387 (2020).Article CAS PubMed PubMed Central Google Scholar Download referencesAcknowledgementsThis work was financially supported by the Guangxi Natural Science Foundation (2026GXNSFGA00640007), the National Natural Science Foundation of China (82473348, 82303797), the Guangxi Young Elite Scientist Sponsorship Program (GXYESS2025006), and the Start-up Fund from Shandong Cancer Hospital (rcyj-202603).Author informationAuthor notesThese authors contributed equally: Leiguang Ye, Guo Zhao, Jiaxiu MaAuthors and AffiliationsDepartment of Medical Oncology, Affiliated Tumor Hospital of Harbin Medical University, Harbin, ChinaLeiguang YeClinical Trial Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, ChinaGuo ZhaoState Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, ChinaJiaxiu MaResearch Center of Nanomedicine Technology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, ChinaQianqian Gan, Na Luo, Dingyu Pan, Chunxi Chen & Shipeng NingCenter for Nuclear Medicine and Molecular Imaging (CNMMI), Shandong Cancer Hospital and Institute, Jinan, ChinaXiaoyuan ChenAuthorsLeiguang YeView author publicationsSearch author on:PubMed Google ScholarGuo ZhaoView author publicationsSearch author on:PubMed Google ScholarJiaxiu MaView author publicationsSearch author on:PubMed Google ScholarQianqian GanView author publicationsSearch author on:PubMed Google ScholarNa LuoView author publicationsSearch author on:PubMed Google ScholarDingyu PanView author publicationsSearch author on:PubMed Google ScholarChunxi ChenView author publicationsSearch author on:PubMed Google ScholarXiaoyuan ChenView author publicationsSearch author on:PubMed Google ScholarShipeng NingView author publicationsSearch author on:PubMed Google ScholarContributionsAll authors contributed extensively to the work presented in this paper. S.P.N. and X.Y.C. conceived and edited the paper. L.G.Y., G.Z., J.X.M., Q.Q.G., N.L., D.Y.P., and C.X.C. conducted the literature survey, G.Z. and L.G.Y. prepared the original draft and figures and collated the expert advice from the coauthors, and S.P.N. and X.Y.C. revised the paper. All authors have read and approved the review article.Corresponding authorsCorrespondence to Xiaoyuan Chen or Shipeng Ning.Ethics declarationsConflict of interestX.C. is a co-founder of and holds shares in Yantai Lannacheng Biotechnology Co., Ltd. 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