VSIG4 Restricts Hepatocellular Carcinoma Control by Suppressing Tumor-Specific CD8+ T-cell Immunity in the Tumor Microenvironment

Immunotherapies have revolutionized the treatment of hepatocellular carcinoma (HCC), yet their response rates remain limited, highlighting the need for new therapeutic targets. In this study, we found that VSIG4 (V-set and immunoglobulin domain containing 4) is predominantly expressed by macrophages in both mouse and human HCC, with high VSIG4 expression correlating with poor prognosis in HCC patients. In autochthonous HCC models, VSIG4 deficiency in mice promoted tumor-specific CD8+ T cell abundance, intratumoral infiltration, and effector function in the tumor microenvironment, resulting in better tumor control and significantly enhanced efficacy of anti-PD-L1 and anti-VEGF combination treatments. Furthermore, we observed that VSIG4+ macrophages colocalize with CD8+ T cells in HCC, and that VSIG4 directly mediates T cell suppression in ex vivo and in vitro studies. These findings suggest that VSIG4 is a critical inhibitor of anti-tumor immunity in HCC and may be targeted for improved immunotherapies.