Abstract 895: A systemically administrated STING agonist in albumin formulation activated neutrophils for anti-cancer immunotherapy

Abstract Background: Neutrophils, the most abundant leukocytes (50-70%) in human circulation, are key players in the innate immune response and increasingly recognized for their multifaceted roles in cancer biology. Beyond their established functions in infection control and inflammation, they have been shown to significantly influence tumor progression through complex interactions within the tumor microenvironment. Neutrophils exhibit remarkable phenotypic heterogeneity and plasticity, which allows them to adopt either tumor-suppressing or tumor-promoting functions. How to program neutrophils in vivo for anti-cancer therapy? We developed a systemically administrated STING agonist formulated within albumin formulation to activate neutrophils for anti-cancer immunotherapy. Methods & Results: We synthesized a novel non-nucleotide STING agonist dimer ZSA-51D encapsulated in albumin nanoparticles (nano ZSA-51D), which exhibited a potent STING pathway activation in THP1-BlueTM ISG cells (EC 50 0.44 nM) and mouse myeloid cells (EC 50 < 10 nM). Interestingly, we found the Nano ZSA-51D highly activated CD101-CD14+ and CD101+CD14+ neutrophils in vitro and in vivo, which was STING pathway dependent. The pharmacokinetic studies in mice shown Nano ZSA-51D highly accumulated in bone marrow (BM). Most of the Nano ZSA-51D were absorbed by neutrophils in BM, blood and Tumor, which resulted in high neutrophil activation in vivo. The Nano ZSA-51D plus α-PD1 achieved complete remission in the MC-38 colon cancer and robust anti-cancer effects in pancreatic cancer model. The tumor immune cell infiltration was examined by flow cytometry at 24 h after treatments. We found the neutrophils were highly activated in BM and blood, then the activated (CD101-CD14+ and CD101+CD14+) neutrophils largely infiltrated into tumor after Nano ZSA-51D treatment. The bulk mRNA sequence analysis showed the neutrophils were activated through Toll-like receptor, TNF-α and NF-κB signaling pathway. Surprisingly, the activated CD101-CD14+ and CD101+CD14+ neutrophils enhanced the antigen presentation of exogenous peptide antigen via MHC class I, further promote the proliferation and activation of T cells, which shown robust anti-cancer effects in vivo after rejected the activated neutrophils into tumor. Conclusion: In this study, we developed a novel systemically administered STING agonist formulated within albumin formulation (Nano ZSA-51D) to activate neutrophils for anti-cancer immunotherapy. Nano ZSA-51 plus α-PD1, demonstrated superior anticancer efficacy through activating neutrophil to promote the proliferation and activation of T cells in vivo. Citation Format: Jinsong Tao, Hongyi Zhao, Chengyi Li, Zhongwei Liu, Hanning Wen, Qiuxia Li, Miao He, Bo Wen, Fang Ke, Wei Gao, Duxin Sun. A systemically administrated STING agonist in albumin formulation activated neutrophils for anti-cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 895.