USP14-mediated metabolic competition impairs CD8+ T cell immunosurveillance in hepatocellular carcinoma
Abstract
Hepatocellular carcinoma (HCC) frequently develops resistance to CD8+ T cell–based immunotherapy, yet the mechanisms driving this immune evasion remain poorly understood. To identify tumor-intrinsic regulators of immunotherapy resistance and explore therapeutic strategies to restore T cell–mediated tumor control, we employed three functional genomics approaches using in vitro and in vivo CRISPR screening. Cancer USP14 was identified as the critical immune evasion driver. USP14-high HCC patients exhibited poorer anti-PD1 antibody therapy responses and reduced CD8+ T cell infiltration. Inhibition of USP14 suppressed HCC cell growth in coculture with activated CD8+ T cells and restored cocultured CD8+ T cell cytotoxicity. In vivo USP14 targeting synergized with anti-PD1 antibody therapy. Mechanistically, USP14 deubiquitinated and stabilized GLUT1 through the removal of Lys-48-linked ubiquitin chains at Lys-245, which enabled HCC cells to outcompete CD8+ T cells for glucose, generating a glucose-deprived tumor microenvironment that suppressed CD8+ T cell function. Our findings show USP14 in cancer has a proimmunoevasive role in CD8+ T cell–based tumor immunity through GLUT1-mediated glucose competition. These findings position USP14 inhibitors as promising adjuvants to enhance immunotherapy efficacy in HCC, providing actionable insights for overcoming resistance.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (11)
Yichuan Yuan
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Yi Niu
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Zhenkun Huang
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Yunxing Shi
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Zhu Lin
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Dinglan Zuo
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Chengrui Zhong
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Kai Li
Xin-Yuan Guan
Department of Clinical Oncology, The University of Hong Kong
Yunfei Yuan
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center
Binkui Li
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research for Cancer, Sun Yat-sen University Cancer Center