Abstract 2002: Intravenously administered STING agonist-loaded positively charged liposomes selectively target tumor microenvironments and reprogram tumor vasculature

Abstract Introduction: The stimulator of interferon genes (STING) signaling pathway activates type I interferon (IFN) in antigen-presenting cells to promote T cell priming and activation. STING agonists have shown great potential in preclinical studies, but they are not applicable for most patients due to limited systemic delivery. Therefore, we designed a positively charged liposome loaded with STING agonist (PoSTING) for systemic delivery of STING agonists and to selectively target tumor immunity and tumor vasculature. Method: We designed PoSTING using 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 18:0 PEG2000 PE (PEG-PE), and 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). The properties and stability of PoSTING were evaluated by dynamic light scattering, transmission electron microscopy, and high-performance liquid chromatography. PoSTING (1 mg/kg) was administered intravenously to Lewis lung carcinoma (LLC)-bearing mouse models every three days. Tumor tissues were comprehensively analyzed by histologic, flow cytometric, and Nanostring immune profiling assays. Results: PoSTING efficiently loaded 88.5% of STING agonists. The average particle size was 198.4 nm, which avoided clearance by the mononuclear phagocyte system. PoSTING could fuse with cell membrane of target cells due to a positive surface charge (+44.53 mV). Stability tests found that PoSTING could be stored at 4°C for 12 weeks and remained stable in serum for a week. Intravenously administered PoSTING selectively accumulated in LLC tumor tissues and suppressed tumor growth. In particular, PoSTING was preferentially accumulated in tumor endothelial cells and perivascular cells, and suppressed tumor angiogenesis and normalized abnormal tumor vasculatures. PoSTING also increased expression levels of P-selectin, which is involved in endothelial-lymphocyte interactions and prepares tumor vessels for lymphocyte trafficking. PoSTING induces type I IFN responses in antigen-presenting cells, tumor ECs, and cancer cells, and promotes intratumoral infiltration of CD8+ T cells by remodeling tumor microenvironment. In addition, PoSTING significantly upregulated genes related to type I/II IFNs, Th1/Th2 responses, innate/adaptive immunity, and chemokines. Conclusion: PoSTING is a novel and stable systemic delivery platform that effectively and selectively delivers STING agonists to tumor tissue, triggering vascular normalization and immune reprogramming. Citation Format: Eun-Jin Go, Hannah Yang, Wooram Park, Won suk Lee, So Jung Kong, Seung Joon Lee, Dong Keun Han, Hong Jae Chon, Chan Kim. Intravenously administered STING agonist-loaded positively charged liposomes selectively target tumor microenvironments and reprogram tumor vasculature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2002.