---
title: "mRNA LNP co-delivery of autoactivated cGAS and membrane-tethered IL-12 induces systemic tumor cont"
id: "biorxiv-1-combining-an-autoactivated-cgas-mutant-with-membrane-tethered-il-12-via-mrna"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-1-combining-an-autoactivated-cgas-mutant-with-membrane-tethered-il-12-via-mrna"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1?rss=1"
published_at: "2026-10-16T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# mRNA LNP co-delivery of autoactivated cGAS and membrane-tethered IL-12 induces systemic tumor cont
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-1-combining-an-autoactivated-cgas-mutant-with-membrane-tethered-il-12-via-mrna
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1?rss=1)
- **Published At:** 2026-10-16T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Investigators engineered an mRNA lipid nanoparticle (LNP) platform to co-deliver an autoactivated **cGAS** mutant (cGASR241E) and membrane-tethered **IL-12** (IL-12TM) into tumors. - The study team observed that cGASR241E mRNA LNPs autonomously produced cyclic GMP-AMP in vivo, activating host **STING** signaling and initiating antitumor responses. - Co-administration with IL-12TM mRNA LNPs led to localized cytokine production and a reduction in regulatory T cells within the tumor microenvironment. - Data indicated restoration of effector function in tumor-infiltrating T cells after combination therapy, linking innate sensing to adaptive T cell reinvigoration. - The combination elicited systemic antitumor immunity and suppressed distal (non-treated) tumors across multiple mouse models, according to the authors. - Therapeutic efficacy required **CD8+ T cells** and **IFNg** signaling in the host; the source reported these dependencies without further mechanistic dosing details. - The combination improved responsiveness to **PD-L1** blockade in the reported experiments. - The source did not report detailed dosing regimens, LNP composition specifics, mouse strain details, or the exact experimental timelines in the abstract; those methodological details are absent from the provided source text. - Authors framed this approach as a clinically translatable strategy to integrate cGAS-STING activation with cytokine-driven T cell programming for systemic tumor control.
## Clinical Analysis & Structured Key Points
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Anli Zhang 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Anli%2BZhang%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Zhang%20A&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAnli%2BZhang%2B) Yan Fang 2 Harvard Medical School * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Yan%2BFang%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Fang%20Y&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AYan%2BFang%2B) Ruoshi Peng 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Ruoshi%2BPeng%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Peng%20R&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ARuoshi%2BPeng%2B) Minglu Yan 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Minglu%2BYan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Yan%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMinglu%2BYan%2B) Zihang Chen 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Zihang%2BChen%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Chen%20Z&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AZihang%2BChen%2B) Tuo Li 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Tuo%2BLi%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Li%20T&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ATuo%2BLi%2B) Jiaxing Tan 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Jiaxing%2BTan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Tan%20J&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AJiaxing%2BTan%2B) Lijun Sun 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Lijun%2BSun%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Sun%20L&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3ALijun%2BSun%2B) Zhijian Chen 1 UT Southwestern Medical Center; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Zhijian%2BChen%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Chen%20Z&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AZhijian%2BChen%2B) * For correspondence: zhijian.chen@utsouthwestern.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5874115/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5874115/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5874115/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5874115/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.10.15.759215v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5874115/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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. ### Competing Interest Statement L.S. is an employee of ImmuneSensor Therapeutics. Z.J.C. is a scientific collaborator with ImmuneSensor Therapeutics and a scientific advisor for Brii Biosciences. L.S. and Z.J.C. are inventors of US patents 10,336,786; 10,519,188 and 11,033,635. ## Funder Information Declared Z.J.C was funded by NIH (U54CA244719, R01CA299257), Welch Foundation (I-1389), and Cancer Grand Challenge from CRUK (CGCATF-2021/100023) and NCI (OT2CA278683). A.Z was funded by Lymphoma Research Foundation, Breast Cancer Alliance and Susan G. Komen Foundation. Z.J.C is an investigator of the HHMI. Y.F. was supported by the NCI Predoctoral to Postdoctoral Fellow Transition Award (F99CA274647/K00CA274647) Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a [CC-BY-NC 4.0 International license](http://creativecommons.org/licenses/by-nc/4.0/). bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. 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