Metabolic trapping of arachidonic acid by Treg cells shapes CD8+ T cell anti-tumor immunity

ABSTRACT: Regulatory T (Treg) cells rely on lipid metabolism to thrive in the lipid-rich tumor microenvironment (TME), but whether this metabolism shapes the extracellular metabolite landscape that acts on effector T cells remains unknown. Here, we identify epoxide hydrolase 1 (Ephx1), highly expressed in tumor-infiltrating Treg cells, as a cell-intrinsic determinant of arachidonic acid (AA) availability in the TME. Treg-specific deletion of Ephx1 induced compensatory, ACSL4-dependent incorporation of exogenous AA, converting Treg cells into a metabolic trap for tumor-derived AA and lowering its extracellular abundance. The resulting AA scarcity restored the mitochondrial fitness of CD8⁺ T cells, rewired their metabolism away from fatty acid oxidation toward more efficient energy generation, and skewed exhaustion trajectories toward effector-like intermediate states while preserving the stem-like progenitor pool, collectively restraining tumor progression. In patients with hepatocellular carcinoma, TME AA levels tracked with tumor burden and inversely with the mitochondrial fitness of infiltrating CD8⁺ T cells. Accordingly, intratumoral delivery of the AA-release inhibitor Methyl Arachidonyl Fluorophosphonate (MAFP) reinvigorated CD8⁺ T cell immunity and acted synergistically with anti-PD-1 therapy. Targeting Treg cell lipid metabolism thus offers a route to reprogram the TME metabolome and potentiate cancer immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE352441 | GEO | 2026/10/29

REPOSITORIES: GEO