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We demonstrate that tumors with higher malignancy or stages exert a more pronounced suppression on systemic antitumor immunity. Critically, high tumor burden drives persistent defects in CD8+ T cell\u2010mediated immune memory even after tumor resection, compared to low burden. Through single\u2010cell RNA and T cell receptor sequencing in mouse models, we identify a subset of tumor\u2010reactive Cxcr6+Cd8+ T (TRT) cells whose early activation, expansion, and long\u2010term memory are suppressed in high burden settings, compared to those in low burden settings. Mechanistically, high\u2010burden tumors secrete more CXCL3 than low burden, which promotes expansion of TGF\u03b21+ neutrophils, thereby inhibiting the function of CD8+ TRT cells. Neutrophil depletion reverses this immunosuppression, and CXCL3 antagonism under adjuvant\/neoadjuvant settings restores the activation and long\u2010term memory formation of CD8+ TRT cells impaired by high tumor burden. CXCL3 antagonism synergizes with anti\u2010PD\u20101 therapy, enhancing tumor control in orthotopic and metastatic models. Collectively, the CXCL3\u2010neutrophil\u2010TGF\u03b21 axis is a key mediator of tumor burden\u2010induced systemic immune dysfunction, and CXCL3 antagonism represents a promising strategy to improve immunotherapy outcomes, particularly for patients with locally advanced or advanced disease.<\/jats:p>","DOI":"10.1002\/advs.77976","type":"journal-article","created":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T18:00:31Z","timestamp":1790532031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CXCL3 Antagonism Reverses Systemic Antitumor Immune Memory Impairment Associated With High Tumor Burden and Sensitizes Anti\u2010PD\u20101 Therapy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4929-6220","authenticated-orcid":false,"given":"Ji","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Breast Surgery The First Affiliated Hospital with Nanjing Medical University  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