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

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

We found that MAIT cells lose their effector functions in patients with MASLD and uncover that this dysfunction is driven by MASLD-associated polyunsaturated fatty acids (PUFAs), which selectively accumulate in MAIT cells but not in conventional CD8+ 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 linked to MAIT cell dysfunction was associated with poor survival.

CONCLUSIONS

Our findings identify a novel immunometabolic axis that impairs MAIT cell-mediated anti-cancer immunity in MASLD and may represent a targetable pathway to enhance the effectiveness of immunotherapy.

IMPACT AND IMPLICATIONS: 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.