Transforming role of cancer associated fibroblasts: From therapeutic barriers to promising targets

Tumor microenvironment (TME) serves as a critical mediator in cancer progression and treatment response, with cancer-associated fibroblasts (CAFs) recognized as core regulators of stromal-tumor interactions. As essential components of the TME, CAFs orchestrate tumor progression and therapy resistance through multifaceted mechanisms, including extracellular matrix (ECM) remodeling, angiogenesis modulation, and immune regulation, which collectively establish a complex regulatory network. Owing to their functional heterogeneity and potent tumor-promoting properties, CAFs have emerged as promising targets for novel anti-tumor therapies. This review highlights recent advances in the understanding of CAFs, focusing on their intricate interactions within the TME and their synergistic roles in promoting therapy resistance in cancer. Furthermore, we also discuss current CAF-targeted therapeutic strategies and ongoing clinical trials, and propose future research directions to further advance this field. • Cancer-associated fibroblasts (CAFs) are key regulators of stromal-tumor interactions within tumor microenvironment (TME). • CAFs establish a complex regulatory network within TME through interacting with tumor cells, remodeling extracellular matrix, promoting angiogenesis, and suppressing anti-tumor immunity. • The coordinated actions within TME mediated by CAFs drive resistance to anti-cancer therapies. • Targeting CAFs represents a promising therapeutic avenue in cancer treatment, with several approaches currently under investigation in ongoing clinical trials.