Neutrophil Antigen Presentation Reprograms the Tumor Microenvironment and Elicits Durable and Broad Anti-Tumor Immunity

Immunotherapy often fails in solid tumors due to an immunosuppressive tumor microenvironment, driven in part by dysfunctional dendritic cells impairing antigen presentation, and suppressive neutrophils. Recent studies revealed a non-canonical role for neutrophils in antigen presentation (nAPC), whose frequency in tumors correlates with improved prognosis in several human cancers. Here, we show that an intravenously delivered antibody-antigen-conjugate (AAC) targeting neutrophil FcγRIIIB reprograms neutrophils into nAPCs that drive robust CD8⁺ T cell activation. This response requires neutrophils and their expression of MHC-I and occurs independently of conventional type-1 dendritic cells (cDC1), demonstrating that nAPCs can compensate for cDC1 deficiencies. In a mouse melanoma model, AAC therapy promotes durable immunity limiting metastases of Ova-negative tumors in the lung and contralateral skin, with tumor burden inversely correlating with intratumoral nAPC frequency. AAC treatment efficacy is attributed to tumor infiltration by antigen-specific CD8⁺ T cells, NK cells, and memory TSCM and TRM cells recognizing both the target antigen and melanocyte-lineage antigens, consistent with effective epitope spreading, which could overcome tumor heterogeneity and antigen loss. Mechanistically, the spleen is required for T cell priming and tumor infiltration, suggesting AAC engages a cancer-spleen axis that bypasses the dysfunctional tumor-draining lymph node (LN). Both CD8⁺ T cells and NK cells are essential for tumor control. Co-treatment with anti-PD-1 enhances tumor regression and metastasis control, while anti-PD-1 alone is ineffective. In summary, AAC therapy reprograms neutrophils to initiate potent T cell immunity, offering a novel strategy to break immune exclusion and enhance anti-PD1 therapy in solid tumors.