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

Immunotherapy often fails in solid tumors due to an immunosuppressive tumor microenvironment, driven in part by dysfunctional dendritic cells (DC) impairing antigen presentation and suppressive neutrophils. Recent studies revealed a noncanonical 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 major histocompatibility complex class I and occurs independently of conventional type 1 DCs (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 stem cell-like and tissue-resident memory T 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 dysfunctional tumor-draining lymph nodes. Both CD8+ T cells and NK cells are essential for tumor control. Anti-PD-1 co-treatment enhances tumor regression and metastasis control, while anti-PD-1 monotherapy is ineffective. In summary, AAC therapy reprograms neutrophils to initiate potent T-cell immunity, offering a novel strategy to break immune exclusion in solid tumors. SIGNIFICANCE: A novel mechanism of neutrophil reprogramming, utilizing an AAC that initiates antigen presentation in the absence of conventional cDCs, offers a translational strategy to overcome immune exclusion in solid tumors.