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

  • Cell Mol Immunol. 2026 May;23(5):491-504. doi: 10.1038/s41423-026-01409-8.
Sicheng Fu  1 ,  Maoyu Tang  2  3 ,  Changfeng Zhao  4 ,  Sanwei Chen  5 ,  Miya Su  4 ,  Jun Pan  4 ,  Yuwei Zhang  4 ,  Xiaohu Wang  4 ,  Wenhao Jia  4 ,  Xinmin Chu  4 ,  Shi Chen  4 ,  Yusheng Chen  3 ,  Lijian Chen  6 ,  Tengchuan Jin  4 ,  Zhigang Tian  4 ,  Yubei Sun  7 ,  Yeben Qian  8 ,  Lianxin Liu  9 ,  Hua Wang  10 ,  Huimin Zhang  11 ,  Li Bai  12  13  14
Affiliations
  • 1. Department of Health Management Center of the First Affiliated Hospital, State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 2. Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
  • 3. Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China.
  • 4. Department of Health Management Center of the First Affiliated Hospital, State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
  • 5. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 6. Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
  • 7. Department of Medical Oncology, Division of Life Sciences and Medicine, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China.
  • 8. Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 9. Department of Hepatobiliary Surgery, State Key Laboratory of Immune Response and Immunotherapy, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 10. Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China. [email protected].
  • 11. Department of Health Management Center of the First Affiliated Hospital, State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 12. Department of Health Management Center of the First Affiliated Hospital, State Key Laboratory of Immune Response and Immunotherapy, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
  • 13. Insitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, China. [email protected].
  • 14. Institute of Artificial Intelligence, Hefei Comprehensive National Science Center, Hefei, China. [email protected].
PMID: 41974917 DOI: 10.1038/s41423-026-01409-8
Abstract

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.

Keywords
CD4+ MAIT; Glycolysis; HCC; MAIT cell plasticity; Metabolic crosstalk; Th17 polarization.
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