Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion

Abstract

Itaconate is a well-known immunomodulatory metabolite; however, its role in hepatocellular carcinoma (HCC) remains unclear. Here, we find that macrophage-derived itaconate promotes HCC by epigenetic induction of Eomesodermin (EOMES)-mediated CD8+ T-cell exhaustion. Our results show that the knockout of immune-responsive gene 1 (IRG1), responsible for itaconate production, suppresses HCC progression. Irg1 knockout leads to a decreased proportion of PD-1+ and TIM-3+ CD8+ T cells. Deletion or adoptive transfer of CD8+ T cells shows that IRG1-promoted tumorigenesis depends on CD8+ T-cell exhaustion. Mechanistically, itaconate upregulates PD-1 and TIM-3 expression levels by promoting succinate-dependent H3K4me3 of the Eomes promoter. Finally, ibuprofen is found to inhibit HCC progression by targeting IRG1/itaconate-dependent tumor immunoevasion, and high IRG1 expression in macrophages predicts poor prognosis in HCC patients. Taken together, our results uncover an epigenetic link between itaconate and HCC and suggest that targeting IRG1 or itaconate might be a promising strategy for HCC treatment.

The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma

“…In terms of FAO, IL4-mediated M2 polarization is counteracted when FAO is inhibited by etomoxir (a clinically approved FAO inhibitor) or CPT1A shRNA [ 81 ]. When decitabine is used to sustain RIPK3 (a vital factor in inflammation and necroptosis) hypomethylation or FAO targeting in RIPK3-KO mice, the anti-tumor immunity of TAMs is elevated and M2 polarization is attenuated, resulting in FA metabolism suppression [ 44 ].…”