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

Xuemei Gu, Haoran Wei, Caixia Suo, Shengqi Shen, Chuxu Zhu, Liang Chen, Kai Yan, Zhikun Li, Zhenhua Bian, Pinggen Zhang, Mengqiu Yuan, Yingxuan Yu, Jinzhi Du, Huafeng Zhang (), Linchong Sun () and Ping Gao ()
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Xuemei Gu: South China University of Technology
Haoran Wei: Southern Medical University
Caixia Suo: South China University of Technology
Shengqi Shen: Guangdong Academy of Medical Sciences
Chuxu Zhu: South China University of Technology
Liang Chen: South China University of Technology
Kai Yan: Guangdong Academy of Medical Sciences
Zhikun Li: South China University of Technology
Zhenhua Bian: South China University of Technology
Pinggen Zhang: University of Science and Technology of China
Mengqiu Yuan: University of Science and Technology of China
Yingxuan Yu: South China University of Technology
Jinzhi Du: South China University of Technology
Huafeng Zhang: University of Science and Technology of China
Linchong Sun: Southern Medical University
Ping Gao: South China University of Technology

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-43988-4

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