Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth
Menée à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel les acides gras oméga 3 suppriment la croissance tumorale en réduisant la sécrétion, par les macrophages associés à la tumeur, de cytokines pro-inflammatoires de la famille de l'interleukine IL-6
Dietary polyunsaturated fatty acids (PUFAs) shape inflammatory signaling within the pancreatic tumor microenvironment (TME), but the cellular mechanisms underlying their effects on tumor progression remain unclear. Using orthotopic models of pancreatic ductal adenocarcinoma (PDAC), we show that omega-3 (n-3) and omega-6 (n-6) PUFAs are differentially incorporated into tumor lipid pools, generating spatially heterogeneous lipid microenvironments. While an n-6–enriched diet accelerated PDAC growth, an n-3–enriched diet suppressed tumor growth in a T cell-independent manner. Examining inflammatory effects in PDAC tumors, the n-3 PUFA–enriched diet reduced pro-inflammatory cytokines, including IL-6 family members, and single-cell and spatial analyses identified tumor-associated macrophages (TAMs) as the primary diet-responsive population. Indeed, selective conversion of n-6 to n-3 fatty acids within myeloid cells using an inducible fat-1 transgene, which encodes an n-3 desaturase that converts n-6 to n-3 PUFAs in vivo, was sufficient to suppress tumor growth, whereas fibroblast-restricted conversion had no effect. This finding is the first to formally establish that cellular origin of PUFA metabolism within the TME is a key determinant of tumor progression and identifies TAMs as critical mediators of n-3–dependent tumor suppression. Furthermore, the n-3 PUFA–enriched diet reduced Arg1+ immunosuppressive TAMs and promoted C1q+ and MHC-II+ antigen-presenting TAM populations enriched for antigen processing machinery and T cell–recruiting chemokines, alongside reduced IL-6 family cytokine production. Together, these findings establish macrophages as key mediators of n-3–driven tumor control and define a mechanism by which dietary lipids remodel cytokine signaling in the PDAC microenvironment.
Proceedings of the National Academy of Sciences , article en libre accès, 2026