文献类型：期刊文献

英文题名：USP20 promotes CD8+ T cell exhaustion and impairs KRASG12D inhibitor efficacy by orchestrating cholesterol metabolism and autophagy in pancreatic cancer

作者：Yu, Zeyuan[1,2];Qing, Huiguo[1,3];Wang, Tian[1,3,4];Xing, Zongrui[4];Hou, Yansong[1,3,4];Ma, Yong[1];Wang, Tao[1];Chen, Shigong[1,3,4];Shi, Wengui[5,6];Qin, Long[5,7];Dong, Yuman[5,6];Li, Mingdou[1,3,4];Zhao, Rongrong[6];Ye, Zhenzhen[7,8];Feng, Yao[9,10];Zhou, Huinian[1];Yang, Xiaojun[8];Jiang, Xiangyan[1,2];Chen, Rufu[10];Jiao, Zuoyi[1,2]

第一作者：Yu, Zeyuan

通信作者：Yu, ZY[1];Jiang, XY[1];Jiao, ZY[1];Yu, ZY[2];Jiang, XY[2];Jiao, ZY[2];Chen, RF[3]

机构：[1]Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China;[2]Lanzhou Univ, Gansu Prov Basic Discipline Res Ctr Canc Immunol, Lanzhou, Gansu, Peoples R China;[3]Lanzhou Univ, Clin Med Sch 2, Lanzhou, Gansu, Peoples R China;[4]Lanzhou Univ, Dept Gen Surg, Hosp 1, Lanzhou, Gansu, Peoples R China;[5]Lanzhou Univ, Cuiying Biomed Res Ctr, Hosp 2, Lanzhou, Gansu, Peoples R China;[6]Lanzhou Univ, Dept Infect Dis, Hosp 1, Lanzhou, Gansu, Peoples R China;[7]Gansu Univ Chinese Med, Sch Clin Med 1, Lanzhou, Gansu, Peoples R China;[8]Gansu Prov Peoples Hosp, Dept Gen Surg, Lanzhou, Gansu, Peoples R China;[9]Peking Univ, Sch Basic Med Sci, Beijing, Peoples R China;[10]Southern Med Univ, Dept Pancreas Ctr, Guangzhou, Guangdong, Peoples R China

第一机构：Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China

通信机构：[1]corresponding author), Lanzhou Univ, Hosp 2, Dept Gen Surg, Lanzhou, Gansu, Peoples R China;[2]corresponding author), Lanzhou Univ, Gansu Prov Basic Discipline Res Ctr Canc Immunol, Lanzhou, Gansu, Peoples R China;[3]corresponding author), Southern Med Univ, Dept Pancreas Ctr, Guangzhou, Guangdong, Peoples R China.

年份：2026

外文期刊名：GUT

收录：;Scopus(收录号：2-s2.0-105043545257);WOS:【SCI-EXPANDED(收录号:WOS:001811845900001)】；

基金：This work was supported by National Natural Science Foundation of China (82360601 to ZeY and 824B2080 to YM), Major Science and Technology Innovation Project of the Gansu Provincial Health Commission (GSWSQNPY2024-14 to ZeY), the Young Scientists Fund of the National Natural Science Foundation of China 82600018 (to XJ), the Postdoctoral Fellowship Program and China Postdoctoral Science Foundation under grant number 2025M782036 (to XJ), and the Key Incubation Project Funds of the Second Hospital and Clinical Medical School, Lanzhou University (2025-23-zdfy-016 to ZeY, 2025-21-zdfy-014 to ZeY).

语种：英文

外文关键词：PANCREATIC CANCER; MOLECULAR TARGETED THERAPY; IMMUNE RESPONSE

摘要：Background The application of the novel KRASG12D inhibitor in pancreatic ductal adenocarcinoma (PDAC) is currently hindered by adaptive resistance. Metabolic reprogramming is a hallmark of KRASG12D signalling, yet the mechanisms linking these alterations to immunosuppression and low therapeutic response are poorly defined.Objective To identify the key regulatory nodes connecting KRASG12D-driven metabolic adaptations to tumour microenvironment and develop a mechanistic-based combinatorial strategy.Design We integrated whole-exome sequencing, untargeted metabolomics and single-cell RNA sequencing of human PDAC specimens to analyse the metabolic-immune landscape. We evaluated therapeutic efficacy using the autochthonous mouse and patient-derived xenograft models.Results We found that KRASG12D enhanced cholesterol metabolism and promoted CD8+ T cell exhaustion, whereas KRASG12D inhibition or cholesterol synthesis blockade induced compensatory ULK1-associated autophagy. Cotargeting cholesterol metabolism and autophagy potentiated the antitumour efficacy of the KRASG12D inhibitor MRTX1133 and alleviated CD8+ T cell exhaustion. Mechanistically, KRASG12D transcriptionally upregulated USP20 via EGR1, which simultaneously deubiquitinated and stabilised 3-hydroxy-3-methylglutaryl-CoA reductase and ULK1, thereby orchestrating cholesterol metabolism and autophagy-associated survival. Genetic depletion or pharmacological inhibition of USP20 with GSK2643943A suppressed these pathways and restored CD8+ T cell function, improving responses to MRTX1133 and anti-programmed cell death protein-1 (anti-PD-1). In preclinical PDAC models, triple therapy with GSK2643943A, MRTX1133 and anti-PD-1 elicited a robust therapeutic response and induced significant tumour regression.Conclusion USP20 acts as a critical metabolic checkpoint that orchestrates CD8+ T cell exhaustion and therapeutic response. Targeting the USP20-cholesterol-autophagy axis represents a promising strategy to reverse immune suppression and unlock the full potential of KRASG12D inhibitors in PDAC.