2. Academic Validation
  3. VCP downstream metabolite glycerol-3-phosphate (G3P) inhibits CD8+T cells function in the HCC microenvironment

VCP downstream metabolite glycerol-3-phosphate (G3P) inhibits CD8+T cells function in the HCC microenvironment

  • Signal Transduct Target Ther. 2025 Jan 24;10(1):26. doi: 10.1038/s41392-024-02120-8.
Cheng Cheng # 1 2 3,  Qingrui Zha # 1 2 3,  Linmao Sun # 1 2 3,  Tianming Cui # 1 2 3,  Xinyu Guo 2 3,  Changjian Xing 1 2 3,  Zhengxiang Chen 1 2 3,  Changyong Ji 1 2 3,  Shuhang Liang 2 3 4,  Shengwei Tao 1 2 3,  Junhui Chu 1 2 3,  Chenghui Wu 1 2 3,  Qi Chu 1 2 3,  Xuetian Gu 1 2 3,  Ning Zhang 2 3,  Yumin Fu 1 2 3,  Shumin Deng 1 2 3,  Yitong Zhu 1 2 3,  Jiabei Wang 5 6 7,  Yao Liu 8 9 10,  Lianxin Liu 11 12 13
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China.
  • 2 Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China.
  • 3 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China.
  • 4 Department of Gastrointestinal Surgery, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China.
  • 5 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. jbwang16@ustc.edu.cn.
  • 6 Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China. jbwang16@ustc.edu.cn.
  • 7 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China. jbwang16@ustc.edu.cn.
  • 8 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. liuyao66@ustc.edu.cn.
  • 9 Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China. liuyao66@ustc.edu.cn.
  • 10 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China. liuyao66@ustc.edu.cn.
  • 11 Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China. liulx@ustc.edu.cn.
  • 12 Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, Anhui, 230001, China. liulx@ustc.edu.cn.
  • 13 Anhui Provincial Clinical Research Center for Hepatobiliary Diseases, Hefei, Anhui, 230001, China. liulx@ustc.edu.cn.
  • # Contributed equally.
PMID: 39848960 DOI: 10.1038/s41392-024-02120-8
Abstract

CD8+T cells within the tumor microenvironment (TME) are often functionally impaired, which limits their ability to mount effective anti-tumor responses. However, the molecular mechanisms behind this dysfunction remain incompletely understood. Here, we identified valosin-containing protein (VCP) as a key regulator of CD8+T cells suppression in hepatocellular carcinoma (HCC). Our findings reveal that VCP suppresses the activation, expansion, and cytotoxic capacity of CD8+T cells both in vitro and in vivo, significantly contributing to the immunosuppressive nature of the TME. Mechanistically, VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), leading to the accumulation of glycerol-3-phosphate (G3P), a downstream metabolite of GPD1L. The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase Lck, a critical component of the T-cell receptor (TCR) signaling pathway in CD8+T cells. This interaction heightens the phosphorylation of Tyr505, a key inhibitory residue, ultimately reducing Lck activity and impairing downstream TCR signaling. Consequently, CD8+T cells lose their functional capacity, diminishing their ability to fight against HCC. Importantly, we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8+T cells, suggesting synergistic therapeutic potential. These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME, positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12861
    99.90%, p97 AAA ATPase/VCP Inhibitor
    p97
  • HY-15713
    99.92%, VCP/p97 Inhibitor
    p97