# A novel gene therapy approach targeting STING-silenced cold tumors

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $180,425

## Abstract

Project Summary
Tumor immune suppression represents a major obstacle in achieving effective cancer
immunotherapy. The goal of this exploratory project is to develop a novel mRNA-lipid
nanoparticle (mRNA-LNP)-based immunotherapy to overcome this challenge in pancreatic
cancer, one of the deadliest malignancies. Currently, few effective treatments are available for
pancreatic cancer. The majority of pancreatic cancers are also resistant to immune checkpoint
blockade. Thus, novel therapeutic strategies are needed to target this lethal cancer. Most
pancreatic cancers display a highly immunosuppressive tumor microenvironment (TME).
Tumor-infiltrating effector CD8+ T cells are critical for improved patient survival, and yet they are
either absent or sparse in the majority of pancreatic cancers, indicating an intrinsic mechanism
that impedes T cell infiltration and activation. We recently discovered that Stimulator of
Interferon Genes (STING) is silenced in pancreatic and other cancers. Because STING function
is critical for stimulating antitumor T cell responses, our finding suggests that STING silencing
contributes to the immunologically “cold” TME. We found that reactivating STING upregulates
cytokines/chemokines that are crucial for promoting intratumoral T cell infiltration. More
importantly, reactivation of STING specifically kills STING-silenced cancer cells. Because tumor
antigens released by dying cancer cells in vivo could be engulfed by antigen-presenting cells to
generate systemic antitumor response and amplify tumoricidal effect, we hypothesize that
targeted reactivation of STING in pancreatic cancer could invigorate the immune-dampened
TME and improve tumor immunogenicity. In this project, we will develop mRNA-LNP to
specifically deliver permanently active STING mutants into pancreatic cancer to bolster T cell
antitumor cytotoxicity. This approach aims to overcome the limitations of traditional STING
agonists, which lack tumor specificity and do not work in STING-silenced cancers. To define
their efficacy in stimulating antitumor immunity, the STING mRNA-LNP will be tested in vitro and
in an orthotopic syngeneic murine pancreatic cancer model, which faithfully recapitulates the
immunobiologically “cold” TME of pancreatic cancer. We will also combine STING mRNA-LNP
with PD-1 blockade to circumvent pancreatic cancer resistance to the immune checkpoint
therapy and spur synergistic antitumoral activity. These preclinical studies have the potential for
developing a novel immunotherapy to overcome immune resistance and improve treatments for
a diverse array of STING-silenced cancers that are refractory to current therapies.

## Key facts

- **NIH application ID:** 10752705
- **Project number:** 5R21CA267803-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jianxin You
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $180,425
- **Award type:** 5
- **Project period:** 2022-12-09 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10752705

## Citation

> US National Institutes of Health, RePORTER application 10752705, A novel gene therapy approach targeting STING-silenced cold tumors (5R21CA267803-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10752705. Licensed CC0.

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