Cancer-associated fibroblasts and extracellular matrix remodeling driving drug resistance and immune evasion in bladder cancer: research progress

Drug resistance and immune evasion remain major obstacles to the effective treatment of bladder cancer. Cancer-associated fibroblasts (CAFs) are key stromal cells that reshape the tumor microenvironment through extracellular matrix (ECM) deposition and the secretion of cytokines, growth factors, and extracellular vesicles. These activities increase matrix stiffness, alter drug distribution, and restrict immune-cell infiltration and function. This review examines how CAF-driven ECM remodeling contributes to drug resistance and immune evasion in bladder cancer. We focus on collagen deposition and crosslinking, hyaluronic acid accumulation, dysregulated matrix degradation, and associated signaling pathways, including TGF-β, Hedgehog, Wnt, and Notch. We also discuss emerging therapeutic strategies targeting CAFs or ECM components, including matrix-modifying agents, advanced drug-delivery systems, and combination immunotherapies. By integrating mechanistic, translational, and clinical evidence, this review summarizes the current understanding of the CAF–ECM axis and identifies the principal uncertainties that must be addressed before stromal-directed approaches can be incorporated into bladder cancer treatment.