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bioRxiv · 10.64898/2026.10.15.759215

Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control

Zhang, A.·Fang, Y.·Peng, R.·Yan, M.·Chen, Z.·Li, T.·Tan, J.·Sun, L.
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Abstract

Local tumor therapies rarely induce systemic immunity capable of controlling metastatic disease. Here, we engineer an mRNA lipid nanoparticle (LNP) platform to coordinate innate immune sensing and T cell activation in situ through co-delivery of an autoactivated cyclic GMP-AMP synthase mutant (cGASR241E) and membrane-tethered IL-12 (IL-12TM). cGASR241E mRNA LNPs autonomously generated cyclic GMP-AMP in vivo, activating host STING signaling and initiating antitumor responses. Co-administration with IL-12TM mRNA LNPs promoted localized cytokine production, reduced regulatory T cells, and restored effector function in tumor-infiltrating T cells. This combination elicited systemic antitumor immunity and suppressed distal tumors across multiple mouse models. The therapeutic efficacy required CD8+ T cells and IFNg; signaling in host, supporting a model in which innate DNA sensing is coupled to IL-12-mediated T cell functional reinforcement. In addition, the combination enhanced responsiveness to PD-L1 blockade. Together, these findings establish a clinically translatable strategy to integrate cGAS-STING activation with cytokine-driven T cell programming to drive systemic tumor control.

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Zhang, A., Fang, Y., Peng, R., Yan, M., Chen, Z., Li, T., Tan, J., Sun, L.. 2026-10-16. Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control. https://doi.org/10.64898/2026.10.15.759215

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