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

  • Br J Cancer. 2025 Sep;133(5):697-708. doi: 10.1038/s41416-025-03089-z.
Banglun Pan  #  1 ,  Siyan Chen  #  2 ,  Zhu Zhang  #  1 ,  Dongjie Ye  1 ,  Xiaoxia Zhang  1 ,  Yuxin Yao  1 ,  Yue Luo  1 ,  Hao Wu  1 ,  Xiaoqian Wang  1 ,  Nanhong Tang  3  4  5  6
Affiliations
  • 1. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
  • 2. Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China.
  • 3. Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China. [email protected].
  • 4. Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China. [email protected].
  • 5. Key Laboratory of Clinical Laboratory Technology for Precision Medicine (Fujian Medical University), Fujian Province University, Fuzhou, China. [email protected].
  • 6. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China. [email protected].
  • # Contributed equally.
PMID: 40588513 DOI: 10.1038/s41416-025-03089-z
Abstract

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.

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