Jinglong Guo

Supplementary Fig. 8. Characteristics of WT littermate control and Vsig4-/- Kupffer cells in culture, Raji-VSIG4 cells, and human CD8+ T cell suppression by VSIG4-Ig

Supplementary Fig. 4. Immune cells in the livers of Vsig4-/- and WT littermate control mice harboring 4-week MYC/NRASV12/SB11 HCC

Supplementary Fig. 5. CD4+ T cell intratumoral infiltration and IFNγ production in Vsig4-/- vs WT littermates 4 weeks after MYC/NRASV12/SB11 HCC induction

Supplementary Fig. 7. Vsig4-/- mice show improved priming of antigen-specific CD8+ T cells in the antigen-expressing liver

Supplementary Fig. 1. VSIG4 is expressed in hepatic macrophages in both mouse and human healthy livers and HCC

Supplementary Fig.9. Significant reduction of HCC burden in Vsig4-/- mice treated with the combination of anti-PD-L1 and anti-VEGF antibodies.

Supplementary Fig. 6. IHC staining for mouse livers with HCC 4 weeks after HTVi of MYC/NRASV12/SB11 plasmids

Supplementary Fig. 2. Validation of the MYC/NRASV12/SB11 HCCs between Vsig4-/- and WT littermate control mice

Supplementary Fig. 3. Four-week and 7-week MYC/NRASV12/SB11 HCC burden and survival of HTVi-based MYC/β-Catennin/SB11 HCC model in Vsig4-/- and WT littermate control mice

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 V-set and immunoglobulin domain–containing 4 (VSIG4) is predominantly expressed by macrophages in both mouse and human HCC, with high VSIG4 expression correlating with poor prognosis in patients with HCC. 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 antitumor immunity in HCC and may be targeted for improved immunotherapies.