Cancer-associated fibroblasts: The silent conductors of tumor evolution and therapy refractoriness

Cancer-associated fibroblasts (CAFs) are key elements of the tumor microenvironment and influence cancer growth, progression, metastasis, and treatment resistance. They originate from multiple sources, including resident fibroblasts, stellate cells, epithelial and endothelial cells, and bone marrow-derived precursors, leading to substantial functional and molecular diversity. Most CAF subsets promote tumor development by remodeling the extracellular matrix, releasing growth factors and cytokines, inducing epithelial-mesenchymal transition, and suppressing antitumor immunity. However, some subsets can restrain tumor growth. This heterogeneity makes therapeutic targeting difficult. This review summarizes current knowledge of CAF origins, activation mechanisms, molecular markers, and functional subtypes, emphasizing their contributions to an immunosuppressive tumor microenvironment that limits the effectiveness of immunotherapy. It also discusses emerging therapeutic strategies such as CAF depletion, phenotype reprogramming, and extracellular matrix normalization, along with their potential benefits and challenges.