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<p>Regulatory T cells (Tregs) contribute to the immune escape of hepatocellular carcinoma (HCC). However, the drivers of the accelerated Treg accumulation in HCC remain unclear. In this study, Treg infiltration-related genes were analysed, and proteasome activator subunit 3 (PSME3) was identified as a pivotal driver using bioinformatics analysis. Functional experiments were performed to investigate the correlation between PSME3 expression and programmed cell death-1 (PD-1) monoclonal antibody therapy resistance in HCC. Elevated levels of PSME3 lead to metabolic reprogramming towards glycolysis and upregulation of osteopontin (OPN) expression. This glycolysis-induced OPN secretion by HCC cells promotes the differentiation and enrichment of Tregs while inhibiting CD8<sup>+</sup> T cells in vivo and in vitro. Mechanistically, PSME3 enhanced PTEN-FBXL7 binding and promoted PTEN degradation through FBXL7-mediated ubiquitination, thereby enhancing glycolysis. The combination of PSME3 inhibition and PD-1 blockade is a promising strategy for HCC treatment. In conclusion, our data showed the critical role played by PSME3 in triggering Treg infiltration and inducing anti-PD1 tolerance.</p>

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PSME3 drives Tregs infiltration and anti-PD1 resistance in hepatocellular carcinoma by regulating FBXL7/PTEN-mediated metabolic reprogramming

  • 期刊论文

  • 发表日期：

    2025年10月15日

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  • Qiuyang Chen,
  • Yuan Liang,
  • Yu Li,
  • Xiangyu Li,
  • Jinren Zhou,
  • Xiaozhang Xu,
  • Qing Shao,
  • Qufei Qian,
  • Tianning Huang,
  • Ziyan Song,
  • Maruyama Takashi,
  • Minjie Lin,
  • Ling Lu,
  • Jian Gu

摘要

Regulatory T cells (Tregs) contribute to the immune escape of hepatocellular carcinoma (HCC). However, the drivers of the accelerated Treg accumulation in HCC remain unclear. In this study, Treg infiltration-related genes were analysed, and proteasome activator subunit 3 (PSME3) was identified as a pivotal driver using bioinformatics analysis. Functional experiments were performed to investigate the correlation between PSME3 expression and programmed cell death-1 (PD-1) monoclonal antibody therapy resistance in HCC. Elevated levels of PSME3 lead to metabolic reprogramming towards glycolysis and upregulation of osteopontin (OPN) expression. This glycolysis-induced OPN secretion by HCC cells promotes the differentiation and enrichment of Tregs while inhibiting CD8+ T cells in vivo and in vitro. Mechanistically, PSME3 enhanced PTEN-FBXL7 binding and promoted PTEN degradation through FBXL7-mediated ubiquitination, thereby enhancing glycolysis. The combination of PSME3 inhibition and PD-1 blockade is a promising strategy for HCC treatment. In conclusion, our data showed the critical role played by PSME3 in triggering Treg infiltration and inducing anti-PD1 tolerance.