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

Affiliations

• 1. Hepatic Surgery Center, and Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.
• 2. Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.
• 3. Chinese Cooperative Group of Liver Cancer (CCGLC), Chinese Chapter of International Hepato-Pancreato Biliary Association, Wuhan 430000, Hubei, P. R. China.
• 4. National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430071, Hubei, China.
• 5. Department of Gastroenterology, and Institute of Liver and Gastrointestinal Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, P. R. China.

PMID: 40577442 DOI: 10.1126/sciimmunol.ado3485

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.

在肝细胞癌（HCC）中，免疫治疗的总体应答率并不高，且免疫治疗耐药机制尚未被完全阐明。我们的研究显示，在HCC中，E3泛素连接酶Riplet会因启动子高甲基化而普遍沉默。Riplet的缺失会调控脂肪酸代谢，进而促进CD8 T细胞的终末耗竭。具体而言，Riplet的缺失会阻碍脂肪酸合酶（FASN）的K48 连接多泛素化，从而加速HCC中的脂肪酸生成。肿瘤细胞产生的游离脂肪酸（尤其是棕榈酸/PA/C16:0）会通过增强T细胞中信号转导及转录激活因子3（STAT3）的棕榈酰化来激活STAT3，最终引发CD8 T细胞的终末耗竭。缺乏Riplet的HCC细胞对抗PD-1治疗具有耐药性，而使用FASN抑制剂进行治疗则能克服这种耐药性。我们的研究揭示了Riplet如何通过改变脂质代谢来诱导CD8 T细胞耗竭及抗PD-1耐药性，这为治疗Riplet缺陷型HCC患者的联合疗法提供了思路。

Keywords: HCC, Riplet, FASN, PD-1, CD8 T cell, STAT3；

关键词：肝癌，肝细胞癌, E3泛素连接酶, 脂肪酸合酶, 程序性死亡受体1, CD8 T细胞, 信号转导及转录激活因子3，T细胞耗竭，PD-1耐药，肿瘤耐药，重组蛋白，重组抗体，兔多克隆抗体，流式抗体，InVivoMAb，佰乐博，佰乐博生物