Ciobu, N.;Kumari, R.;Kumar, J.;Balaseviciute, U.;Iftesum, M.;Mitchell, J.;Ruiz, J.;Flowers, S.;Nishikawa, K.;Cano-Segarra, G.;Vila-Escoda, A.;Xiao, Y.;Phoebe, A.;Navaridas, R.;Steffani, M.;Gannamedi, D.;Jin, J.;Cogliati, B.;Saoi, M.;Ly, R.;Ogidigo, J.;Rodriguez-Silva, M.;Pardo, M.;Pokrifka, E.;Almanza, L.;Tiano, S.;Bush, E.;Nandakumar, R.;Abou-Alfa, G.;Pinyol, R.;Monetti, M.;Lombard, D.;Bayik, D.;Watson, D.;Wang, X.;Jones, P.;Stockwell, B.;Schwabe, R.;Galligan, J.;Romesser, P.;David, Y.;Gartia, M.;Llovet, J.;Sanghvi, V.

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8⁺ T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant ω-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain ω-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8⁺ T cells via lipid peroxidation. FADS2 inhibition restores CD8⁺ T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinson’s disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8⁺ T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.