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

Area of Science:

• Immunology
• Cancer Biology
• Hematology

Background:

• Tumor-infiltrating immunosuppressive neutrophils (PMN-MDSCs) hinder cancer immunotherapy.
• Neutrophil development can be influenced at the hematopoietic stem and progenitor cell (HSPC) stage.

Purpose of the Study:

• To investigate if a STING agonist can reprogram HSPCs into antitumor neutrophils.
• To evaluate the potential of this approach to enhance cancer immunotherapy.

Main Methods:

• Treatment of HSPCs and neutrophils with an albumin-bound STING agonist (Nano ZSA-51D).
• Analysis of neutrophil differentiation, phenotype (CD14+, ICAM-1+), and function.
• Assessment of immune responses, including CD8+ T cell activation and MHC I presentation.
• Evaluation of therapeutic efficacy in colon and pancreatic cancer models, alone and in combination with α-PD1 therapy.

Main Results:

• Nano ZSA-51D expands HSPCs and directs them towards neutrophil development.
• The agonist reprograms neutrophils into a CD14+ICAM-1+ subset via STING-NF-κB-TNF-α signaling, enhancing tumor infiltration and activity.
• Reprogrammed neutrophils exhibit increased interferon signaling and MHC I presentation, boosting CD8+ T cell responses.
• Combined treatment with Nano ZSA-51D and α-PD1 therapy achieved complete remission in colon tumors and showed efficacy in pancreatic cancer models.

Conclusions:

• Targeting early hematopoiesis offers a strategy to generate antitumor neutrophils.
• Nano ZSA-51D reprograms HSPCs to produce neutrophils that enhance anti-tumor immunity.
• This approach holds promise for improving cancer immunotherapy, particularly in immune-resistant settings.