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 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.