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Figure 1. Roles of cancer-associated fibroblasts (CAFs) in cancer drug resistance. CAFs affect almost all cancer treatments, including traditional chemotherapy, targeted therapy, and immunotherapy. There are various mechanisms, such as secretion of growth factors, production of extracellular vesicles, and metabolites, through which CAFs promote drug resistance. Chemoresistance is enhanced by secreted factors from CAFs. Among them, TGF-β2 and IL-6/IL-8 from CD10⁺GPR77⁺ CAFs induce GLI2 upregulation and NF-κB activation, respectively, to maintain the stemness of cancers. IL-6 and/or IL-8 from CAFs were also found to induce EMT or chromatin remodeling in cancer cells. Upon stimulation with cytokines, such as IL-6, IL-8, NRG1, and HGF, the response to targeted therapies can be undermined by BRD4 modification, HER3 signaling activation, and MAPK and PI3K/AKT activation. Furthermore, CAFs mitigate tumor immunity by polarizing macrophages into the M2 phenotype, suppressing the function of NK and T cells and oncolytic viruses through Chi3L1, TGF-β, NetG1, CXCL12, IL-1α/β, and IFN-β1. Although appealing, targeting CAFs remains a big challenge today. The efforts to define CAF subtypes and further decipher their functions in the microenvironment may shed light on discovering new targeting strategies and provide more benefits to cancer patients. EMT: Epithelial-to-mesenchymal transition; CAF: cancer-associated fibroblast.