Albumin-STING Nanocomplex Reprograms HSPCs to Antitumor Neutrophils with Enhanced MHC I Antigen Presentation for Cancer Immunotherapy

Abstract Recent evidence suggests that reprogramming hematopoietic stem and progenitor cells (HSPCs) into distinct neutrophil subsets could improve cancer immunotherapy. Although STING activation in dendritic cells and macrophages is well studied to enhance antitumor immunity, it is unknown whether and how STING activation can direct HSPCs toward antitumor neutrophils for cancer immunotherapy. Here, we developed an albumin-STING agonist nanocomplex (Nano ZSA-51D) that reprogramed HSPCs into CD14⁺ICAM-1+ neutrophils with enhanced MHC I antigen presentation. Nano ZSA-51D expanded HSPCs and skewed differentiation toward granulocyte-monocyte progenitors via STING-NF-κB-IL-6 signaling. It further reprogrammed immature (CD101-) and mature (CD101+) neutrophils into activated CD14⁺ICAM-1+ subsets through STING-NF-κB–TNF-α signaling. These neutrophils migrated from bone marrow to tumors for MHC I antigen presentation to activate tumor-specific CD8+ T cell immunity. Adoptive transfer of immature/activated CD14⁺ neutrophils combined with α-PD1 led to complete tumor regression of colon tumors. Nano ZSA-51D combined with α-PD1 achieved potent anticancer efficacy in colon and pancreatic cancer model with minimal toxicity. This study establishes Nano ZSA-51D as a novel strategy to reprogram HSPCs into antitumor neutrophils that mediate MHC I antigen presentation to activate CD 8+ T cell tumor immunity. One Sentence Summary: Albumin-STING agonist nanocomplex reprograms HSPCs into CD14⁺ICAM-1+ neutrophils that enhance MHC I-mediated tumor-specific CD 8+ T cell immunity.