FGFR4 promotes CAF activation through the CXCL10-CXCR3 axis in colon cancer.

Cancer-associated fibroblasts (CAFs) promote the malignant phenotype of cancer through crosstalk with tumor and immune cells within the tumor microenvironment. Therefore, the mechanisms underlying CAF activation require in-depth study to develop strategies targeting CAFs during cancer immunotherapy. In this study, we investigated the role of FGFR4 in CAF regulation in colon cancer. FGFR4-overexpressing cancer cells promoted CAF abundance and activation in vivo, while also inducing the differentiation of normal fibroblasts into CAFs via their secretome. Mechanistically, FGFR4 induced CXC-chemokine ligand (CXCL) 10 production by upregulating Toll-like receptor 3-interferon regulatory factor-interferon beta (IFNβ) signaling and the autocrine action of IFNβ. CXCL10 increased CAF marker expression in fibroblasts, including alpha-smooth muscle actin and vimentin. CXCL10 also promoted CAF migration, invasion, and contractibility, which reflects CAF activation. In contrast, knocking down CXCL10 or neutralizing antibodies abolished CAF marker expression in fibroblasts. Inhibition of CXC receptor type (CXCR) 3, the cognate receptor of CXCL10, also impaired CAF function. In human colon cancer samples, FGFR4 and CXCL10 expression was positively correlated with CAF marker expression. Finally, dual inhibition of FGFR4 and CXCR3 suppressed tumor growth, accompanied by CAF downregulation. Our findings reveal the mechanism through which FGFR4 promotes CAF differentiation/activation in TME via the CXCL10-CXCR3 axis, highlighting the potential of co-targeting FGFR4 and CXCR3 as a therapeutic strategy for patients with stromal-dominant tumors.