Tumor arachidonic acid synthesis impairs metabolic fitness of CXCR6+ resident memory CD8+ T cells and drives immunotherapy resistance in hepatocellular carcinoma

Abstract Lipid metabolic reprogramming in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) drives immunosuppression, yet the critical mediators orchestrating tumor-immune crosstalk remain elusive. Here, we identify arachidonic acid (ARA), synthesized via the rate-limiting enzyme FADS1, as a novel oncometabolite that accumulates in TME and fuels hepatocarcinogenesis. Genetic or pharmacological inhibition of FADS1 attenuates ARA level, thereby enhancing CD8+ T cell infiltration and cytotoxicity. Using CRISPR-Cas9 screening of metabolic genes in T cell differentiation, we uncover the ARA pathway as a negative regulator of liver-resident memory CD8+ T cells (TRM). These CXCR6+ TRM exhibit antigen specificity but are impaired by FADS1 overexpression or ARA exposure, compromising anti-tumor immunity during tumor rechallenge. Mechanistically, ARA specifically disrupts IL-15-dependent metabolic fitness in CXCR6+ TRM. Therapeutically, targeting the FADS1-ARA axis synergizes with anti-PD-1 and GPC3-CAR-T therapies. Thus, our study identifies a promising target for ARA-enriched immunosuppressive TME, aiming to improve the effectiveness of immunotherapies in HCC.