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

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.