J Natl Cancer Cent. 2025 Mar 27;5(3):237-251. doi: 10.1016/j.jncc.2025.03.002. eCollection 2025 Jun.ABSTRACTThe resistance to cancer treatment is a major clinical obstacle, being strongly influenced by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are critical elements of the TME. CAFs are heterogeneous and are activated through diverse pathways. These CAFs engage in reciprocal interactions with tumor cells, driving tumor progression and therapeutic resistance. In this review, we discuss the role of CAFs in the development of tumor resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Besides, we summarize recent clinical trials in CAF-targeted therapies. The development of resistance involves physical barrier formation, metabolic reprogramming, exosome release, DNA repair, bypass pathway activation, multidrug resistance protein upregulation, and immune checkpoint inhibition. Challenges remain in addressing drug resistance despite the therapeutic potential of targeting CAFs: the cellular origins of CAFs need to be clarified, and their limited clinical applications need to be increased. Future studies should focus on elucidating the reasons for CAF heterogeneity, developing precise targeting strategies, and validating the clinical safety and efficacy of CAF-based therapies to overcome treatment resistance and improve patient outcomes.PMID:40693233 | PMC:PMC12276570 | DOI:10.1016/j.jncc.2025.03.002