Liang Junnan, Liao Jingyu, Chang Ruizhi, Jia Wenlong, Li Ganxun, Chen Zeyu, Wu Hang, Zhu Chang, Wen Jingyuan, Huang Qibo, Gao Han, Gui Zichen, Xu Weiqi, Liang Huifang, Liu Qiumeng, Xu Dafeng, Li Zifu, Xia Limin, Chen Xiaoping, Huang Zhao, Zhang Wanguang, Ding Zeyang, Zhang Bixiang
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.
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.
Sci Immunol. 2025 Jun 27;10(108):eado3485. doi: 10.1126/sciimmunol.ado3485.
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 is universally silenced by promoter hypermethylation in HCC. Loss of 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.
免疫疗法对肝细胞癌（HCC）的总体反应率不高，且免疫疗法的耐药机制尚未完全明确。我们报告称，E3泛素连接酶在HCC中因启动子高甲基化而普遍沉默。其缺失会调节脂肪酸代谢，促进CD8 T细胞的终末耗竭。Riplet缺失会阻碍脂肪酸合酶（FASN）的K48连接的多聚泛素化，从而加速HCC中的脂肪酸生成。肿瘤细胞衍生的游离脂肪酸，尤其是棕榈酸（PA/C16:0），通过增强T细胞中信号转导和转录激活因子3（STAT3）的棕榈酰化来激活STAT3，从而引发CD8 T细胞的终末耗竭。缺乏Riplet的HCC细胞对抗PD-1疗法耐药，而用FASN抑制剂治疗可克服耐药性。我们的研究表明Riplet如何改变脂质代谢并诱导CD8 T细胞耗竭和抗PD-1耐药，从而为治疗缺乏Riplet的HCC患者的联合疗法提供了途径。
