Background: Innate immune pathway of stimulator of interferon genes (STING) orchestrates antitumor immune responses and can elicit potent antitumor efficacy. However, clinical development of cyclic-dinucleotide (CDN) STING agonists is mostly limited to intratumoral administration because of the undesirable pharmacological properties of CDN. This limits their applications in treating metastasis, hematologic malignancies, and hard-to-reach solid tumor. Here, we aim to develop a pharmacological formulation that facilitate systemic delivery of CDN STING agonist to broaden its applications for cancer treatment.

Methods: Nutritional metal ions physiologically mediate various immune processes, which could potentially be utilized for modulating the STING pathway. By screening different nutritional metal ions, we discovered manganese ion (Mn2+) and cobalt ion (Co2+) synergize with CDN STING agonists and significantly enhance type-I interferon (IFN-I) responses. As Mn2+ has been used in FDA approved drugs, we further developed the formulation to enable systemic codelivery of Mn2+ and CDN.

Results: Mn2+ could significantly potentiate the STING activation by up to 77-fold. In addition, Mn2+ interact with CDNs and self-assemble into nanocrystals that could be stabilized as uniform nanoparticles (~120 nm) through lipid layer coating (CDN-Mn Particle, CMP). After either intratumoral or intravenous administrations, CMP effectively elevate the serum levels of inflammatory cytokines (IFN-β, TNF-α, CXCL-9, and CXCL-10), mitigates the suppressive functions of myeloid cells, relieve the immunosuppressive tumor microenvironment (TME), and induce antigen-specific CD8+ T cells expansion. Minute dose of CMP given intravenously exert remarkable antitumor efficacy in CT26, B16F10, and immune checkpoint blocker (ICB)-resistance tobacco-associated NOOC1 murine tumor models, leading to efficient tumor regression. Furthermore, the systemic biodistribution of CMP could be modulated by changing the composition of the lipid layer coating, allowing for organ-specific delivery of CMP to target tumor malignancies in certain organs.

Conclusions: CMP provides a novel and versatile platform for local and systemic cancer treatment. More importantly, it highlights the potential of harnessing metal ions in treating various immune-mediated diseases.

Citation Format: Xingwu Zhou, Xiaoqi Sun, Wang Gong, Yu Leo Lei, James J. Moon. Amplifying STING activation by cyclic dinucleotide-manganese particles for systemic cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 314.