Abstract B015: Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control

Abstract Local cancer treatments are often effective in controlling primary tumor growth. However, the abscopal effect induced by local treatment—critical for treating metastatic tumors—is rarely achieved and particularly challenging in less immunogenic tumors. Here, we report that local administration of lipid nanoparticles (LNPs) containing mRNAs encoding an autoactivated cyclic GMP-AMP (cGAMP) synthase (cGAS) R241E mutant and membrane-tethered IL-12 (IL-12TM) induces potent local and systemic tumor control in multiple non-immunogenic murine models, including B16 and TC-1 tumors. The cGAS R241E mutant but not wild-type cGAS mRNA LNPs spontaneously produce cGAMP in vivo and predominately activate conventional DC1, enhancing innate immune sensing and inhibiting tumor growth in a host STING-dependent manner. IL-12TM mRNA LNPs synergize with cGAS R241E mRNA LNPs to promote local IFN-γ production while minimizing systemic exposure compared to soluble IL-12 mRNA LNPs. Mechanistically, combining cGAS R241E and IL-12TM mRNA LNPs (Combo) enhances dendritic cell activation and stimulates antigen-specific CD8+ T cells within the tumor, facilitating their migration to draining lymph nodes. While the multiple immune cell populations contribute to anti-tumor efficacy against local tumors, CD8+ T cells and intact IFN-γ signaling are responsible for distal tumor control. Additionally, Combo treatment synergizes with PD-L1 checkpoint blockade to further reduce distal tumor burden. Taken together, these findings demonstrate that mRNA LNP-mediated delivery of the autoactivated cGAS mutant and IL-12TM provides a safe and effective strategy for treating both primary and metastatic tumors. Citation Format: Anli Zhang, Zhijian (James) Chen. Local delivery of mRNA lipid nano particles encoding an autoactivated cGAS mutant and membrane-tethered IL-12 enhances local and distal tumor control [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B015.