# Precision Engineering of STING-DC Immunity to Overcome Tumor Immune Evasion

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $984,000

## Abstract

Abstract
 Host defense responses by the mammalian immune system can be very potent but require
exquisite spatio-temporal coordination. This coordination is essential to match the immune activity
to the specific threat, to monitor and regulate the immune response, minimize damage to normal
tissues, and terminate the response when the hazard is eliminated. Stimulator of interferon genes
(STING) is an endoplasmic reticulum-associated signaling protein that is essential for
transcriptional regulation of numerous host defense genes against malignant cells. STING is
activated by 2’, 3’-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an
endogenous secondary messenger, which is produced by cGAMP synthase (cGAS) in response
to cytosolic DNA as a danger signal. Despite potent antitumor activities demonstrated by STING
agonists in preclinical studies, early clinical trials have yet to show significant antitumor response
in cancer patients. Current STING agonist designs are ‘always ON’, leading to on-target, off-tumor
toxicity in healthy tissues. The proposed R35 program will integrate four areas of research to
harness this important natural defense mechanism and innovate a safe and efficacious STING-
targeted therapy for immune-resistant cancers. In nanotechnology, we will design and synthesize
a (pH-hypoxia) AND logic nanoparticle STING agonist that stays protected in normal tissues but
will be activated in response to acidic pH and hypoxia signals inherent in the tumor
microenvironment. This ensures minimal toxicity in healthy tissues, while promoting targeted
STING activation within malignancies. In STING signaling, we will employ cryo-electron
microscopy to investigate the synergy of PSC7A with cGAMP for STING binding and activation.
In dendritic cell biology, we will investigate STING-mediated transformation of hematopoietic
progenitor cells into conventional type 1 dendritic cells (cDC1), and define its ramifications on
antitumor immunity. In immune-oncology, we will employ patient-derived tumor fragments to probe
into STING agonists' roles in immune resistant tumors. Furthermore, we will assess the prognostic
value of the STING-cDC1 signature in forecasting therapeutic responses to treatments like
STING-targeted interventions and checkpoint blockade therapies. Through our bench-to-clinic
and back-to-bench approach, our goal is to pinpoint the barriers that have stymied effective
targeting of this crucial biological pathway, and ultimately apply these insights to establish a
successful STING-targeted therapy in cancer patients unresponsive to current treatments.

## Key facts

- **NIH application ID:** 10982765
- **Project number:** 1R35CA294010-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Jinming Gao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $984,000
- **Award type:** 1
- **Project period:** 2024-09-01 → 2031-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10982765

## Citation

> US National Institutes of Health, RePORTER application 10982765, Precision Engineering of STING-DC Immunity to Overcome Tumor Immune Evasion (1R35CA294010-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10982765. Licensed CC0.

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