Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control
- 1UT Southwestern Medical Center
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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BibTeX
@misc{zhang2026combining,
title = {{Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control}},
author = {A. Zhang and Y. Fang and R. Peng and M. Yan and Z. Chen and T. Li and J. Tan and L. Sun and Z. Chen},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.15.759215},
url = {https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Combining an autoactivated cGAS mutant with membrane-tethered IL-12 via mRNA lipid nanoparticles promotes systemic tumor control
AU - A. Zhang
AU - Y. Fang
AU - R. Peng
AU - M. Yan
AU - Z. Chen
AU - T. Li
AU - J. Tan
AU - L. Sun
AU - Z. Chen
PY - 2026
DA - 2026/10/15
PB - bioRxiv
DO - 10.64898/2026.10.15.759215
UR - https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1
AB - 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.
ER -