A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

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.

doi:10.64898/2026.06.25.734592

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bioRxiv · 10.64898/2026.06.25.734592

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

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Abstract

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 {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-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 Parkinsons 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.

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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.. 2026-06-26. A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer. https://doi.org/10.64898/2026.06.25.734592

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