{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:09:53Z","timestamp":1791558593498,"version":"4.3.4"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"108","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Immunol."],"published-print":{"date-parts":[[2025,6,27]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Riplet<\/jats:italic>\n                    is universally silenced by promoter hypermethylation in HCC. Loss of\n                    <jats:italic toggle=\"yes\">Riplet<\/jats:italic>\n                    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\u2013derived 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\u2013PD-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\u2013PD-1 resistance, thus suggesting avenues for combined therapies for treating patients with Riplet-deficient HCC.\n                  <\/jats:p>","DOI":"10.1126\/sciimmunol.ado3485","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T14:01:01Z","timestamp":1751032861000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":52,"title":["Riplet promotes lipid metabolism changes associated with CD8 T cell exhaustion and anti\u2013PD-1 resistance in hepatocellular carcinoma"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4855-6756","authenticated-orcid":true,"given":"Junnan","family":"Liang","sequence":"first","affiliation":[{"name":"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. 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