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However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid\u2013neutrophil\u2013adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPAR\u03b1 activation, leading to T-cell suppression. Using AB928, a dual A2aR\/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.<\/jats:p>","DOI":"10.64898\/2026.04.02.716169","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T22:30:13Z","timestamp":1775514613000},"source":"Crossref","is-referenced-by-count":0,"title":["Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine"],"prefix":"10.64898","author":[{"given":"Rashi","family":"Singhal","sequence":"first","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8012-0246","authenticated-orcid":false,"given":"Nina W.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Molecular and 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