Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti–PD-1 resistance in hepatocellular carcinoma

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-06-27 DOI:10.1126/sciimmunol.ado3485

Junnan Liang, Jingyu Liao, Ruizhi Chang, Wenlong Jia, Ganxun Li, Zeyu Chen, Hang Wu, Chang Zhu, Jingyuan Wen, Qibo Huang, Han Gao, Zichen Gui, Weiqi Xu, Huifang Liang, Qiumeng Liu, Dafeng Xu, Zifu Li, Limin Xia, Xiaoping Chen, Zhao Huang, Wanguang Zhang, Zeyang Ding, Bixiang Zhang

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Abstract

The overall response rate to immunotherapy is modest in hepatocellular carcinoma (HCC), and immunotherapy resistance mechanisms are incompletely understood. We report that the E3 ubiquitin ligase Riplet is universally silenced by promoter hypermethylation in HCC. Loss of Riplet modulates fatty acid metabolism to promote terminal exhaustion of CD8 T cells. Riplet loss impedes K48-linked polyubiquitination of fatty acid synthase (FASN), consequently accelerating fatty acid production in HCC. Tumor cell–derived free fatty acids, especially palmitic acid (PA/C16:0), activate STAT3 (signal transducers and activators of transcription 3) by enhancing its palmitoylation in T cells, consequently triggering terminal CD8 T cell exhaustion. HCC cells with Riplet deficiency are resistant to anti–PD-1 therapy, and treatment with an FASN inhibitor overcomes resistance. Our study shows how Riplet can alter lipid metabolism and induce CD8 T cell exhaustion and anti–PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.

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Riplet促进肝细胞癌中与CD8 T细胞衰竭和抗pd -1耐药相关的脂质代谢变化

肝细胞癌（HCC）对免疫治疗的总体反应率一般，免疫治疗耐药机制尚不完全清楚。我们报道了E3泛素连接酶Riplet在HCC中普遍被启动子超甲基化沉默。Riplet的缺失可调节脂肪酸代谢，促进CD8 T细胞的最终衰竭。核糖核酸丢失阻碍了k48相关的脂肪酸合成酶（FASN）的多泛素化，从而加速了HCC中脂肪酸的产生。肿瘤细胞来源的游离脂肪酸，特别是棕榈酸（PA/C16:0），通过增强T细胞中的棕榈酰化，激活STAT3（信号转导和转录激活因子3），从而触发终端CD8 T细胞衰竭。Riplet缺乏的HCC细胞对抗pd -1治疗有耐药性，用FASN抑制剂治疗可以克服耐药性。我们的研究显示了Riplet如何改变脂质代谢，诱导CD8 T细胞耗竭和抗pd -1耐药性，从而为治疗Riplet缺失的HCC患者提供了联合治疗的途径。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.