Metastasis remains the major reason for high mortality of HCC patients. This study was designed to investigate the role of E-twenty-six-specific sequence variant 4 (ETV4) in promoting HCC metastasis and explored new combination therapy strategy for ETV4-mediated HCC metastasis.PLC/PRF/5, MHCC97H, Hepa1-6 and H22 cells were used to establishment of orthotopic HCC Models. Clodronate liposomes were used to clear macrophages in C57BL/6 mice. Gr-1 monoclonal antibody was used to clear myeloid derived suppressor cell (MDSCs) in C57BL/6 mice. Flow cytometry and immunofluorescence were used to detect the changes of key immune cells in tumor microenvironment.ETV4 expression was positively related to higher TNM stage, poor tumor differentiation, microvascular invasion, and poor prognosis in human HCC. Overexpression of ETV4 in HCC cells transactivated programmed death ligand 1 (PD-L1) and chemokine (C-C motif) ligand 2 (CCL2) expression, which increased tumor-associated macrophages (TAMs) and myeloid derived suppressor cells (MDSCs) infiltration and inhibited CD8+T cells accumulation. Knockdown of CCL2 by lentivirus or CCR2 inhibitor CCX872 treatment impaired ETV4-induced TAMs and MDSCs infiltration and HCC metastasis. Furthermore, fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) and hepatocyte growth factor (HGF)/c-MET jointly upregulated ETV4 expression through ERK1/2 pathway. Additionally, ETV4 upregulated FGFR4 expression and downregulation of FGFR4 decreased ETV4-enhanced HCC metastasis, which created a FGF19-ETV4-FGFR4 positive feedback loop. Finally, anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib prominently inhibited FGF19-ETV4 signaling induced HCC metastasis.ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.Here, we reported that ETV4 increased PD-L1 and chemokine CCL2 expression in HCC cells, which resulted in TAMs and MDSCs accumulation and CD8+T cell inhibition to facilitate HCC metastasis. More importantly, we found that anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib markedly inhibited FGF19-ETV4 signaling mediated HCC metastasis. This preclinical study will provide a theoretical basis for the development of new combination immunotherapy strategies for HCC patients.Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.