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Using pancreatic stellate cell-tumor organoid coculture models and single-cell RNA sequencing analyses, we uncover that hypoxia-driven fibroblast reprogramming promotes immunosuppressive macrophage phenotypes in PDAC. Mechanistically, hypoxia acts through tumor-fibroblast crosstalk to increase IL-6 expression in fibroblasts; in turn, fibroblast-derived IL-6 induces expression of arginase 1 (ARG1), a key mediator of immunosuppression, in macrophages via activation of the JAK\/STAT signaling pathway. Consistent with these findings, macrophages enriched for hypoxia signatures are strongly associated with elevated immunosuppression programs and IL6\/JAK\/STAT3 signaling signatures in PDAC. Our study reveals a paracrine mechanism by which hypoxia coordinates tumor cell, fibroblast, and macrophage interactions to promote immune suppression in PDAC.<\/jats:p>","DOI":"10.3390\/cells15080683","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T13:12:26Z","timestamp":1776085946000},"page":"683","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Hypoxia-Induced Fibroblast IL-6 Promotes Immunosuppressive Macrophage Phenotypes in Pancreatic Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2925-4808","authenticated-orcid":false,"given":"Sean","family":"Hannifin","sequence":"first","affiliation":[{"name":"Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-181X","authenticated-orcid":false,"given":"Ashley M.","family":"Mello","sequence":"additional","affiliation":[{"name":"Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenzin","family":"Ngodup","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nam Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Pasca di Magliano","sequence":"additional","affiliation":[{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3955-7389","authenticated-orcid":false,"given":"Kyoung Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. 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