Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD

作者：Sebastian Deschler, Junika Pohl, Lukas Ramsauer, Philippa Meiser, Sophia Erlacher, Robin Schenk, H. Carlo Maurer, Peng Shen, Juliane Kager, Joseph Zink, Karyna Pistrenko, Enric Redondo Monte, Julius Weber, Lena Wasmaier, Melanie Laschinger, Norbert Hüser, Fabian Geisler, Douglas Thorburn, Hanno Nieß, Gabriela M. Wiedemann, Hans Zischka, Mathias Heikenwälder, Karin Kleigrewe, Carolin Mogler, Jan P. Böttcher, Percy A. Knolle, Roland M. Schmid, Katrin Böttcher · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.06.006 · 被引用次数：30 · 研究领域：Immune Cell Function and Interaction、Ferroptosis and cancer prognosis、Cancer Immunotherapy and Biomarkers

BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells constitute a highly abundant innate-like T-cell population in the human liver that is critical for immune surveillance of hepatic cancers. However, MAIT cells are often dysfunctional in human hepatocellular carcinoma (HCC), for reasons that remain unclear. Here, we aimed to identify the mechanisms driving MAIT cell dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver condition that predisposes patients to HCC. METHODS: We studied MAIT cell functionality, metabolism and anti-cancer activity directly ex vivo in patients with MASLD, as well as in co-culture models mimicking MASLD. (Single-cell) RNA-sequencing was used to translate findings into clinical cohorts of patients with MASLD and MASLD-associated HCC. RESULTS: T cells or NK cells. Mechanistically, PUFAs drive MAIT cell dysfunction through intracellular formation of lipid peroxides that promote a state of 'metabolic exhaustion' characterised by compromised mitochondrial respiration and glycolysis in MAIT cells. Excessive signalling through this MASLD-PUFA-lipid peroxide axis results in MAIT cell death by ferroptosis. Interference with PUFA-induced lipid peroxide formation in MAIT cells reversed their metabolic exhaustion and prevented ferroptotic MAIT cell death, thereby restoring MAIT cell effector function and anti-cancer activity. In patients with HCC, high expression of the MAIT cell-PUFA gene signature that was ...