Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti–PD-1 resistance in hepatocellular carcinoma
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 <i>Riplet</i> is universally silenced by promoter hypermethylation in HCC. Loss of <i>Riplet</i> 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.
Authors
- Zhao Huang (ORCID: https://orcid.org/0000-0002-1151-4942)
- Ruizhi Chang (ORCID: https://orcid.org/0000-0002-0136-926X)
- Wanguang Zhang (ORCID: https://orcid.org/0000-0003-3184-9907)
- Jingyuan Wen
- Chang Zhu (ORCID: https://orcid.org/0000-0001-8263-2041)
- Limin Xia (ORCID: https://orcid.org/0000-0002-6327-6034)
- Zifu Li (ORCID: https://orcid.org/0000-0001-6387-4854)
- Ganxun Li (ORCID: https://orcid.org/0000-0002-2874-8753)
- Weiqi Xu (ORCID: https://orcid.org/0000-0002-4259-0091)
- Qiumeng Liu
- Qibo Huang
- Jingyu Liao
- Zeyu Chen (ORCID: https://orcid.org/0000-0003-1058-8402)
- Zeyang Ding (ORCID: https://orcid.org/0000-0001-5826-0970)
- Xiaoping Chen (ORCID: https://orcid.org/0000-0002-8644-0888)
- Hang Wu (ORCID: https://orcid.org/0009-0001-8485-629X)
- Han Gao (ORCID: https://orcid.org/0000-0002-1474-2107)
- Wenjun Jia (ORCID: https://orcid.org/0000-0003-0170-6729)
- Zichen Gui
- Jia Liang (ORCID: https://orcid.org/0000-0003-4855-6756)
- Huifang Liang (ORCID: https://orcid.org/0000-0001-6874-3634)
- Dafeng Xu
- Bixiang Zhang
Institutions
- Hubei University of Chinese Medicine (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-06-27
- DOI
- https://doi.org/10.1126/sciimmunol.ado3485
- Citations
- 20
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 18.72