The role of cancer-associated fibroblasts in various cancer drug resistance.

Drug resistance remains a principal barrier to effective cancer therapy, with the tumor microenvironment (TME) serving as a central modulator. Among TME components, cancer-associated fibroblasts (CAFs) are the most abundant stromal cells and pivotal orchestrators of tumor initiation, progression, and therapeutic resistance. CAFs promote drug resistance through diverse mechanisms, including secretion of cytokines and chemokines, extracellular matrix remodeling, and direct tumor cell interactions. Accumulating evidence further reveals their multifaceted role in resistance via TME remodeling and dynamic crosstalk with immune and endothelial cells. This review provides a comprehensive synthesis of CAF-mediated drug resistance across multiple malignancies-breast, pancreatic, lung, ovarian, prostate, gastric, and hepatobiliary cancers-and examines how CAFs modulate tumor cell behavior, drug metabolism, efflux pathways, and the broader TME. Emerging CAF-targeted strategies and future therapeutic directions are also discussed, highlighting opportunities to overcome drug resistance and improve clinical outcomes.