The tumor microenvironment (TME) is increasingly recognized as a critical modulator of the initiation, progression, metastasis, and therapeutic resistance of various cancers. Cancer-associated fibroblasts (CAFs), the predominant stromal cell population within the TME, play pivotal roles in these processes through their remarkable phenotypic and functional heterogeneity. Emerging evidence underscores the diversity in the origins, phenotypes, and functions of CAFs, highlighting their ability to adaptively influence tumor biology in a context-dependent manner. CAFs facilitate cancer malignancy via multiple interconnected mechanisms, including the secretion of soluble bioactive factors, the release of exosomes, the metabolic reprogramming of tumor cells, the remodeling of the extracellular matrix (ECM), and the modulation of the immune microenvironment. CAFs have emerged as attractive and viable therapeutic targets. Recent efforts have focused on developing therapies that disrupt the protumorigenic activities of CAFs or reprogram them toward tumor-suppressive phenotypes. Several of these strategies have shown promise and are advancing into clinical trials. In this review, we comprehensively discuss recent advancements in our understanding of the heterogeneity of CAFs, elucidate their multifaceted interactions within the TME, and explore novel therapeutic strategies targeting CAFs across various cancer types. Our review aims to foster the translation of preclinical insights into clinically effective interventions targeting CAFs.
Keywords: Cancer-associated fibroblasts; Crosstalk; Targeted therapy; Tumor microenvironment.
© 2025. The Author(s).