A Promising Cancer Therapy Strategy: Targeting Signaling Pathways Involved in Cancer-Associated Fibroblast Phenotypic Modulation

Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the tumor microenvironment, have attracted increasing attention because of their critical roles in tumor progression and their therapeutic potential. However, owing to the marked heterogeneity of CAFs, distinct CAF subtypes may exert divergent or even opposing functions. Consequently, indiscriminate depletion of CAFs may inadvertently eliminate tumor-restraining subtypes and thereby accelerate tumor progression. In contrast, selectively inhibiting the formation of tumor-promoting CAF subtypes or reprogramming CAFs toward quiescent or tumor-restraining phenotypes is considered a more promising therapeutic strategy. CAF phenotypic modulation is regulated by complex signaling networks, and comprehensive investigation of the underlying pathways may provide novel mechanistic insights and potential therapeutic candidates for CAF-targeted therapy. This review summarizes recent advances in signaling pathways involved in CAF phenotypic modulation and the corresponding targeted agents, with the aim of systematically elucidating CAF phenotypic plasticity and providing new perspectives for future drug development.