CXCL3 Antagonism Reverses Systemic Antitumor Immune Memory Impairment Associated With High Tumor Burden and...

High tumor burden is associated with poorer immunotherapy responses compared to low burden, yet the systemic mechanisms driving this impairment and strategies to reverse it remain unclear. 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-mediated immune memory even after tumor resection, compared to low burden. Through single-cell RNA and T cell receptor sequencing in mouse models, we identify a subset of tumor-reactive Cxcr6+Cd8+ T (TRT) cells whose early activation, expansion, and long-term memory are suppressed in high burden settings, compared to those in low burden settings. Mechanistically, high-burden tumors secrete more CXCL3 than low burden, which promotes expansion of TGFβ1+ 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-term memory formation of CD8+ TRT cells impaired by high tumor burden. CXCL3 antagonism synergizes with anti-PD-1 therapy, enhancing tumor control in orthotopic and metastatic models. Collectively, the CXCL3-neutrophil-TGFβ1 axis is a key mediator of tumor burden-induced systemic immune dysfunction, and CXCL3 antagonism represents a promising strategy to improve immunotherapy outcomes, particularly for patients with locally advanced or advanced disease.