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Here, we investigated the early immune dynamics associated with anti-PD1 responsiveness using longitudinal single-cell transcriptomics, spatial transcriptomics, and neutrophil-specific genetic perturbations in preclinical models of triple-negative breast cancer. We identified a conserved neutrophil interferon-stimulated gene (ISG) program that emerges before overt tumor divergence and predicts resistance to anti-PD1 therapy. Successful treatment was associated with an early reduction of IFN-responsive neutrophils in both blood and tumor tissues, whereas persistent neutrophil IFN signaling correlated with therapeutic resistance. Mechanistically, genetic disruption of either type I or type II interferon signaling in neutrophils enhanced anti-PD1 efficacy and promoted durable anti-tumor immune memory. Spatial analyses further revealed an inverse association between IFN-responsive neutrophils and tertiary lymphoid structure-enriched regions during effective therapy. Together, these findings identify IFN-responsive neutrophils as early determinants of immunotherapy outcome and establish dynamic neutrophil interferon programs as candidate blood-based biomarkers and therapeutic targets for cancer immunotherapy.<\/jats:p>","DOI":"10.64898\/2026.09.30.755684","type":"posted-content","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:10:19Z","timestamp":1790856619000},"source":"Crossref","is-referenced-by-count":0,"title":["Early dynamics of a neutrophil interferon program drive immunotherapy resistance and limit durable anti-tumor immunity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1832-4380","authenticated-orcid":false,"given":"Yang","family":"Gao","sequence":"first","affiliation":[{"name":"Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210, 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