Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth.
9 affiliations
- 1NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037.
- 2Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.
- 3Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232.
- 4Department of Medicine, Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.
- 5Omega-3 and Global Health Institute, Boston, MA 02129.
- 6Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.
- 7Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520.
- 8Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520.
- 9Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599.
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.
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BibTeX
@article{sakuma2026omega3,
title = {{Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth.}},
author = {Stephen Sakuma and Steven Zhao and Andrew Hildreth and Gloria Liu and Valisha Shah and Ming Sun and Shirong Tan and Emily Jacobs and Michael A LaPorta and Jesse Furguiele and Natalia Avina-Ochoa and Anna-Maria Globig and Victoria Tripple and ImmgenT Consortium and Geraldine Maier and Satchidananda Panda and Michelle L Reyzer and Jing X Kang and David W L Ma and Matthew Rodeheffer and Saame Raza Shaikh and Susan M Kaech},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2618288123},
url = {https://europepmc.org/article/MED/42886691},
note = {CC BY},
}
RIS
TY - JOUR
TI - Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth.
AU - Stephen Sakuma
AU - Steven Zhao
AU - Andrew Hildreth
AU - Gloria Liu
AU - Valisha Shah
AU - Ming Sun
AU - Shirong Tan
AU - Emily Jacobs
AU - Michael A LaPorta
AU - Jesse Furguiele
AU - Natalia Avina-Ochoa
AU - Anna-Maria Globig
AU - Victoria Tripple
AU - ImmgenT Consortium
AU - Geraldine Maier
AU - Satchidananda Panda
AU - Michelle L Reyzer
AU - Jing X Kang
AU - David W L Ma
AU - Matthew Rodeheffer
AU - Saame Raza Shaikh
AU - Susan M Kaech
PY - 2026
DA - 2026/10/16
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2618288123
UR - https://europepmc.org/article/MED/42886691
AB - 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.
SN - 0027-8424
SN - 1091-6490
ER -