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

ABSTRACT 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.