Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD
In this study, we identify a novel immunometabolic axis in which polyunsaturated fatty acids, accumulating in liver tissue in MASLD (metabolic dysfunction-associated steatotic liver disease), drive MAIT (mucosal-associated invariant T) cell dysfunction through lipid peroxide-induced metabolic exhaustion and ferroptosis, ultimately impairing their anti-tumour activity. These findings reveal how MASLD creates an immune-permissive environment that may facilitate hepatocellular carcinoma development and progression and prevent effective immunotherapy. Targeting the polyunsaturated fatty acid-lipid peroxide axis could restore MAIT cell function and enhance current immunotherapeutic anti-cancer strategies.
Authors
- Douglas Thorburn (ORCID: https://orcid.org/0000-0002-5610-5448)
- Fabian Geisler (ORCID: https://orcid.org/0000-0003-1545-485X)
- Katrin Böttcher (ORCID: https://orcid.org/0000-0002-4154-8270)
- Junika Pohl (ORCID: https://orcid.org/0009-0003-1749-5812)
- Lukas Ramsauer
- Mathias Heikenwälder (ORCID: https://orcid.org/0000-0002-3135-2274)
- Juliane Kager
- H. Carlo Maurer (ORCID: https://orcid.org/0000-0002-2193-6014)
- Jan P. Böttcher (ORCID: https://orcid.org/0000-0002-8163-8107)
- Sebastian Deschler (ORCID: https://orcid.org/0000-0003-4680-9609)
- Gabriela M. Wiedemann (ORCID: https://orcid.org/0000-0001-6138-9791)
- Roland M. Schmid (ORCID: https://orcid.org/0000-0002-6945-7581)
- Hans Zischka (ORCID: https://orcid.org/0000-0002-4047-1566)
- Robin Schenk (ORCID: https://orcid.org/0000-0001-6823-8128)
- Hanno Nieß (ORCID: https://orcid.org/0000-0002-0981-4049)
- Norbert Hüser (ORCID: https://orcid.org/0000-0003-1521-1970)
- Julius Weber
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Enric Redondo Monte (ORCID: https://orcid.org/0000-0002-3588-223X)
- Percy A. Knolle (ORCID: https://orcid.org/0000-0003-2983-0414)
- Karin Kleigrewe (ORCID: https://orcid.org/0000-0002-7718-0252)
- Philippa Meiser (ORCID: https://orcid.org/0009-0007-9334-1072)
- Karyna Pistrenko
- Sophia Erlacher
- Melanie Laschinger
- Joseph Zink
- Peng Shen
- Lena Wasmaier
Institutions
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- The Royal Free Hospital (GB)
- University Hospital Heidelberg (DE)
- TUM Klinikum (DE)
- Center for Environmental Health (US)
- Helmholtz Zentrum München (DE)
- LMU Klinikum (DE)
- University Children's Hospital Tübingen (DE)
- University College London (GB)
- Technical University of Munich (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Journal of Hepatology
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1016/j.jhep.2025.06.006
- Citations
- 13
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 10.37
Funders
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- Deutsche Krebshilfe