MAIT cell plasticity generates CD4+ MAIT cells that promote HCC progression via metabolic crosstalk with tumor cells.

Mucosal-associated invariant T cells (MAITs) are enriched in the liver and closely related to human hepatocellular carcinoma (HCC), but their role is controversial. Whether and how the plasticity of MAITs modulates HCC progression remain to be explored. Here, we revealed that CD4+ MAITs displaying Th17 features were the major source of IL-17A in human HCC. IL-17A from Th17-polarized CD4+ MAITs promoted HCC progression by enhancing lipid storage and tumor cell proliferation in a PPARα dependent manner. Additionally, we showed that both TCR-dependent and TCR-independent activation signaling induced Th17-polarized CD4+ MAIT differentiation and that strong signaling promoted their differentiation. Moreover, IL-17A production in CD4+ MAITs was promoted by glycolysis via posttranscriptional regulation, and tumor cell-derived kynurenine enhanced glycolysis and IL-17A production through the AHR pathway. These findings demonstrate that the plasticity of MAITs and the generation of CD4+ MAITs promote HCC progression via metabolic crosstalk with tumor cells.