Albumin-Bound STING Agonist Reprograms HSPCs to Antitumor Neutrophils Enhancing CD8+ T Cell Immunity.

Tumor-associated immunosuppressive neutrophils, termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), compromise cancer immunotherapy. Emerging evidence indicates that neutrophil fate can be programmed as early as the hematopoietic stem and progenitor cell (HSPC) stage. Reprogramming HSPCs toward antitumor neutrophils offers a promising therapeutic strategy. Here, we demonstrate that an albumin-bound STING agonist (Nano ZSA-51D) reprograms HSPCs to generate antitumor neutrophils, enhancing MHC I-mediated CD8+ T cell immunity and sensitizing tumors to α-PD1 immunotherapy. Nano ZSA-51D expands HSPCs and reprograms them toward granulocyte-monocyte progenitors for neutrophil development. It further converts immature (CD101-) and mature (CD101+) neutrophils into a CD14+ICAM-1+ subset through STING-NF-κB-TNF-α signaling, enhancing tumor infiltration and antitumor activity. These neutrophils upregulate interferon signaling and MHC I antigen presentation, thereby boosting tumor-specific CD8+ T cell responses. Notably, both adoptive transfer of Nano ZSA-51D-reprogrammed neutrophils and systemic Nano ZSA-51D treatment synergizes with α-PD1 therapy to achieve complete remission of colon tumors through neutrophil- and CD8+ T cell-dependent mechanisms, with potent efficacy also validated in otherwise immune-resistant pancreatic cancer models. Our findings establish a therapeutic strategy to reprogram HSPCs toward antitumor neutrophils, highlighting the potential of targeting early hematopoiesis to rewire neutrophil fate in cancer immunotherapy.