Targeting cancer-associated fibroblasts as a therapeutic strategy to improve immune checkpoint blockade therapy

The tumor microenvironment (TME) significantly influences tumor progression and invasion, with cancer-associated fibroblasts (CAFs) playing pivotal roles in these processes. CAFs contribute to tumor growth, drug resistance, and immune evasion through diverse mechanisms including extracellular matrix (ECM) remodeling, cytokine secretion, and metabolic reprogramming. Clinical evidence increasingly suggests a link between specific CAF subsets and resistance to immune checkpoint blockade (ICB) therapy. This review provides a focused overview of CAF heterogeneity, emphasizing the functional distinction between immunosuppressive subsets [e.g., inflammatory CAFs (iCAFs), myofibroblastic CAFs (myCAFs), FAP⁺ CAFs], and immunostimulatory subsets [e.g., antigen-presenting CAFs (apCAFs), and Meflin⁺ CAFs]. We discuss CAF-related signatures as predictors of ICB response and elucidate mechanisms through which CAFs promote ICB resistance, including upregulation of programmed death-ligand 1 (PD-L1), T-cell exclusion via transforming growth factor-β (TGF-β) and C-X-C motif chemokine 12 (CXCL12), inhibition of T-cell cytotoxicity, and modulation of innate immune cells. Furthermore, we outline preclinical and clinical therapeutic approaches targeting specific CAF subpopulations. We also discuss emerging areas including the role of mitochondrial metabolism, redox regulation, and ferroptosis in CAF-mediated immune evasion. A deeper understanding of CAF molecular biology holds promise for developing novel strategies to overcome ICB resistance.