Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth

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.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-10-16
DOI
https://doi.org/10.1073/pnas.2618288123
Primary Topic
Immune cells in cancer
Type
article
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0.00

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article

Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth

Marc K. Jenkins, David Zemmour, Nicole E. Scharping, Erin Lucas et al.
Proceedings of the National Academy of Sciences
Immune cells in cancer
article

Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth

Marc K. Jenkins, David Zemmour, Nicole E. Scharping, Erin Lucas, M. Kronenberg, Michelle L. Reyzer, Geraldine Maier, Dan Kaplan, Maria‐Luisa Alegre, Satchidananda Panda, Julia Merkenschlager, Saame Raza Shaikh, Kennidy K. Takehara, Antoine Freuchet, Dario Vignali, David W.L., Laurent Gapin, Marion Pepper, Christophe O. Benoist, Rémy Bosselut, Dania Mallah, Stefan Adi Muljo, Susan M. Kaech, Myriam Croze, Valisha Shah, Amir Ferry, Melanie S. Vacchio, Nitya Mehrotra, Rocky Lai, Sam Borys, Sara Mostafavi, Steven Zhao, Laurent Brossay, Claire E. Thefaine, Anna-Maria Globig, Victoria Tripple, Jordan Voisine, Nalat Siwapornchai, Sara E. Hamilton, Sofia Kossida, Natalia Avina-Ochoa, Enxhi Ferraj, Alexandra Cassano, Maurizio Fiusco, Michael A. LaPorta, Jing Xuan Kang, Shirong Tan, Odhran Casey, Ming Sun, Aaron Liu, Alia Welsh, Ken Cadwell, Gloria Liu, Emily Jacobs, Kevin Osum, Jinseok Park, Ian Magill, Stefan Schattgen, Mariya London, Bana Jabri, Nika Abdollahi, Stephen Sakuma, Shanelle Reilly, Paul Thomas, Peter Carbonetto, Gavyn Bee, Iliyan D. Iliev, Lizzie Garcia-Rivera, David Sinclair, Jun R. Huh, Sam Behar, Serge Candéias, Michel Nussenzweig, Sara Quon, Eric Weiss, Jesse Furguiele, Stefani Spranger, Derek Bangs, Andrew Hildreth, Alexander Chervonsky, Charlotte Imianowski, Matthew Stephens, Evelyn Chang, Giovanni Galletti, Joonsoo Kang, Michael Starnbach, Nathan Morris, Olga Barreiro del Rio, Maria Brbic, Katharine Block, Ankit Malik, Ananda Goldrath, Josh Choi, Domenic Abbondanza, Shanshan Zhang, Liang Yang, Andrea Lebron-Figueroa, Matthew Rodeheffer, Siba Smarak Panigrahi
article en

Abstract

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 SciencesVol. 123(42)
University of North Carolina at Chapel Hill (US), Salk Institute for Biological Studies (US), Vanderbilt University (US), Yale University (US), Massachusetts General Hospital (US), Omega Consult (Slovenia) (SI), Department of Health (ZA), University of Guelph (CA)
National Cancer Institute
Good health and well-being
Openalex Percentile: Top 20%
Immune cells in cancer
DOIOpen Access PDFOpenAlex
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