{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037.",
    "Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037.",
    "Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232.",
    "Department of Medicine, Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129.",
    "Omega-3 and Global Health Institute, Boston, MA 02129.",
    "Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada.",
    "Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520.",
    "Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06520.",
    "Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Stephen Sakuma"
    },
    {
      "affs": [
        0
      ],
      "name": "Steven Zhao"
    },
    {
      "affs": [
        0
      ],
      "name": "Andrew Hildreth"
    },
    {
      "affs": [
        0
      ],
      "name": "Gloria Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Valisha Shah"
    },
    {
      "affs": [
        0
      ],
      "name": "Ming Sun"
    },
    {
      "affs": [
        0
      ],
      "name": "Shirong Tan"
    },
    {
      "affs": [
        0
      ],
      "name": "Emily Jacobs"
    },
    {
      "affs": [
        0
      ],
      "name": "Michael A LaPorta"
    },
    {
      "affs": [
        0
      ],
      "name": "Jesse Furguiele"
    },
    {
      "affs": [
        0
      ],
      "name": "Natalia Avina-Ochoa"
    },
    {
      "affs": [
        0
      ],
      "name": "Anna-Maria Globig"
    },
    {
      "affs": [
        0
      ],
      "name": "Victoria Tripple"
    },
    {
      "name": "ImmgenT Consortium"
    },
    {
      "affs": [
        1
      ],
      "name": "Geraldine Maier"
    },
    {
      "affs": [
        1
      ],
      "name": "Satchidananda Panda",
      "orcid": "0000-0002-7855-0091"
    },
    {
      "affs": [
        2
      ],
      "name": "Michelle L Reyzer"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Jing X Kang"
    },
    {
      "affs": [
        5
      ],
      "name": "David W L Ma",
      "orcid": "0000-0002-1165-5972"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Matthew Rodeheffer"
    },
    {
      "affs": [
        8
      ],
      "name": "Saame Raza Shaikh"
    },
    {
      "affs": [
        0
      ],
      "name": "Susan M Kaech",
      "orcid": "0000-0003-1674-1420"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/25b6e6jnngndp.bib",
  "cited_by": 0,
  "doi": "10.1073/pnas.2618288123",
  "fulltext_url": "https://europepmc.org/articles/PMC13684287",
  "id": "25b6e6jnngndp",
  "issns": [
    "0027-8424",
    "1091-6490"
  ],
  "landing_url": "https://europepmc.org/article/MED/42886691",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|Immune cells in cancer"
    ]
  ],
  "openalex": "W7222576912",
  "pdf_url": "https://europepmc.org/articles/PMC13684287?pdf=render",
  "pmcid": "PMC13684287",
  "pmid": "42886691",
  "published": "2026-10-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/25b6e6jnngndp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:46Z",
      "native_id": "MED:42886691",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42886691"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Immune cells in cancer",
      "subfield": "immunology"
    }
  ],
  "title": "Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth.",
  "title_text": "Omega-3 fatty acids reprogram tumor-associated macrophage cytokine signaling and suppress pancreatic cancer growth.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:46Z",
  "url": "https://research.draconitic.com/paper/25b6e6jnngndp",
  "venue": "Proceedings of the National Academy of Sciences of the United States of America",
  "versions": []
}