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Background <p>In hepatitis B virus (HBV)-infected patients, there’s an increase in exhausted T and NK cells, as well as myeloid-derived suppressor cells (MDSCs) in liver, suggesting that boosting immune responses is beneficial. While Vonafexor inhibits HBV transcriptional activity, its effects on the immune microenvironment of HBV-positive hepatocellular carcinoma (HCC) and the mechanisms of immune clearance of these infected cells are not well understood.</p> Methods <p>In this study, tumor tissues from HBV-positive HCC patients were orthotopically transplanted into the livers of Hu-SRC mice to replicate the tumor microenvironment of the patients. Immunofluorescence, flow cytometry, immunoblotting, and RT-qPCR were used to investigate the mechanism by which Vonafexor promoted sublethal damage of virus-positive HCC cells.</p> Results <p>We found that the therapeutic efficacy of Vonafexor in inducing sublethal damage of HBV-positive HCC cells was attributed to its ability to inhibit CD36-mediated free fatty acid intake and enhance GZMB expression in T and NK cells. This effect was mediated through the downregulation of hepatitis B e antigen, which inhibited mitochondrial ROS, thereby augmenting their cytotoxicity via cGAS-STING-NF-κB signaling. Additionally, Vonafexor blocked c-Rel nuclear entry in MDSCs, reducing their infiltration.</p> Conclusions <p>Our study indicated that Vonafexor showed potential as an immunotherapy for HBV-positive HCC.</p> <p></p>

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New mechanistic understanding of FXR agonist Vonafexor: inducing sublethal damage of HBV-positive liver cancer cells via promoting anti-tumor immunity

  • 期刊论文

  • 发表日期：

    2025年6月30日

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  • Banglun Pan,
  • Siyan Chen,
  • Zhu Zhang,
  • Dongjie Ye,
  • Xiaoxia Zhang,
  • Yuxin Yao,
  • Yue Luo,
  • Hao Wu,
  • Xiaoqian Wang,
  • Nanhong Tang

摘要

Background

In hepatitis B virus (HBV)-infected patients, there’s an increase in exhausted T and NK cells, as well as myeloid-derived suppressor cells (MDSCs) in liver, suggesting that boosting immune responses is beneficial. While Vonafexor inhibits HBV transcriptional activity, its effects on the immune microenvironment of HBV-positive hepatocellular carcinoma (HCC) and the mechanisms of immune clearance of these infected cells are not well understood.

Methods

In this study, tumor tissues from HBV-positive HCC patients were orthotopically transplanted into the livers of Hu-SRC mice to replicate the tumor microenvironment of the patients. Immunofluorescence, flow cytometry, immunoblotting, and RT-qPCR were used to investigate the mechanism by which Vonafexor promoted sublethal damage of virus-positive HCC cells.

Results

We found that the therapeutic efficacy of Vonafexor in inducing sublethal damage of HBV-positive HCC cells was attributed to its ability to inhibit CD36-mediated free fatty acid intake and enhance GZMB expression in T and NK cells. This effect was mediated through the downregulation of hepatitis B e antigen, which inhibited mitochondrial ROS, thereby augmenting their cytotoxicity via cGAS-STING-NF-κB signaling. Additionally, Vonafexor blocked c-Rel nuclear entry in MDSCs, reducing their infiltration.

Conclusions

Our study indicated that Vonafexor showed potential as an immunotherapy for HBV-positive HCC.