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Updated: Feb 26, 2026

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

Jinglong Guo1, Siddheshvar Bhela1, Monica Sharma2

  • 1Department of Cancer Immunology, Genentech, South San Francisco, California.

Cancer Immunology Research
|February 25, 2026
PubMed

Insights

V-set and immunoglobulin domain containing 4 (VSIG4) is a novel target in hepatocellular carcinoma (HCC). Inhibiting VSIG4 enhances anti-tumor immunity and improves immunotherapy efficacy in HCC models.

Area of Science:

  • Immunology
  • Oncology
  • Cell Biology

Background:

  • Immunotherapies have transformed hepatocellular carcinoma (HCC) treatment.
  • Limited response rates necessitate novel therapeutic targets for HCC.

Purpose of the Study:

  • To investigate the role of VSIG4 (V-set and immunoglobulin domain containing 4) in HCC.
  • To evaluate VSIG4 as a potential therapeutic target for HCC immunotherapies.

Main Methods:

  • Assessed VSIG4 expression in mouse and human HCC tissues.
  • Utilized autochthonous HCC models to study VSIG4 deficiency effects.
  • Conducted ex vivo and in vitro studies to analyze VSIG4's mechanism of T cell suppression.

Main Results:

  • High VSIG4 expression in HCC correlates with poor patient prognosis.
  • VSIG4 deficiency in mice enhanced CD8+ T cell activity and tumor control.
  • VSIG4+ macrophages were found to suppress CD8+ T cell function in the HCC tumor microenvironment.
  • Combination therapies (anti-PD-L1 and anti-VEGF) showed enhanced efficacy in VSIG4-deficient models.

Conclusions:

  • VSIG4 is predominantly expressed by tumor-associated macrophages in HCC.
  • VSIG4 acts as a direct inhibitor of anti-tumor T cell responses in HCC.
  • Targeting VSIG4 presents a promising strategy for enhancing HCC immunotherapies.

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