FGF19/FGFR4 axis drives immunosuppressive macrophage plasticity in hepatocellular carcinoma

• The expression of FGF19 is closely associated with the infiltration of M2-TAMs in HCC. • FGF19-FGFR4 signaling facilitates the polarization of TAMs towards an M2 phenotype, a process that relies on the activation of the mTOR/S6K/PGC-1α pathway. • The deletion or inhibition of FGFR4 markedly diminishes M2 polarization and the immunosuppressive functions of TAMs. Tumor-associated macrophages (TAMs) predominantly polarize into the M2-like subtype, which is considered an obstacle to immunotherapy for hepatocellular carcinoma (HCC). Aberrant signaling through fibroblast growth factor 19 (FGF19) and its receptor, FGFR4, drives the development and progression of HCC. However, it remains unclear whether this signaling pathway affects the polarization of TAMs in HCC. In our study, we found that HCC samples with high FGF19 levels exhibited increased expression of the M2 marker CD206 compared to those with low FGF19 levels. Notably, FGF19 derived from HCC cells activated FGFR4 on the surface of TAMs, promoting their polarization toward an M2 phenotype, which depends on the activation of the mTOR/S6K/PGC-1α pathway. Furthermore, the deletion or inhibition of FGFR4 significantly reduced M2 polarization and the immunosuppressive functions of TAMs, leading to enhanced anti-tumor immune responses. In conclusion, our study elucidates the molecular mechanisms by which FGF19 promotes M2 polarization of TAMs and suggests a potential therapeutic target for immunotherapy in HCC.