# Deciphering the Roles of STING-Mediated T cell Pyroptosis in Antitumor Immunity

> **NIH NIH R37** · CLEVELAND CLINIC LERNER COM-CWRU · 2024 · $467,502

## Abstract

PROJECT SUMMARY
An immunosuppressive tumor microenvironment presents a significant hurdle in controlling tumor growth.
Activation of the stimulator of interferon genes (STING) protein initiates innate immune responses, potentially
overcoming tumor immunosuppression and eliciting potent antitumor immune responses. However, in clinical
trials, STING agonist therapy has encountered profound tumor resistance, and the mechanisms remain unclear.
There is a significant gap in our understanding of the negative regulatory effects of STING on antitumor immunity
that underlies resistance development in STING agonist therapy. STING is a crucial innate immune sensor that
senses 2’3’-Cyclic GMP-AMP (cGAMP) produced by Cyclic GMP-AMP synthase (cGAS) to activate interferon
(IFN) signaling. Within the complex tumor microenvironment (TME), extracellular cGAMP can be imported into
various cell types, including myeloid cells, Natural Killer (NK) cells, and fibroblasts, inducing STING-mediated
IFN signaling and eliciting potent antitumor immune responses. However, our research has demonstrated that
cGAMP importation into tumor-infiltrating T cells (TILs) can adversely induce STING-mediated cell death of the
T cells, and that this is an important mechanism by which tumors evade immune destruction in mouse tumor
models. Thus, STING activation in the TME both positively and negatively regulates antitumor immunity. These
results lead us to propose the hypothesis that tumors evade T cell mediated immune surveillance through
cGAMP importation into tumor-infiltrating T cells that induces a STING-mediated cell death pathway
independently of IFN. The objective of this project is to elucidate the mechanisms of cGAMP-STING-mediated
T cell death, and to develop strategies for blocking STING-mediated T cell death. Given that STING agonists
are now in development for use as cancer therapeutics, directing activation of STING-mediated IFN signaling
while avoiding STING-mediated death of TILs will improve the success of STING agonist therapy. Aim 1 will
identify cGAMP importers and IFN-induced mediators facilitating cGAMP importation into T cells. Aim 2 will
elucidate the molecular mechanisms underlying cooperative activation of STING with TCR signaling in triggering
T cell pyroptosis. Aim 3 will develop novel immunotherapies via blockade of STING-mediated T cell death. The
proposed studies here will elucidate a novel mechanism by which cGAMP is imported into tumor-infiltrating T
cells to activate STING-mediated cell pyroptosis. We anticipate that the insights gained from our studies will
have a significant impact on STING-based cancer immunotherapies.

## Key facts

- **NIH application ID:** 10854276
- **Project number:** 1R37CA288747-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jianjun Wu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,502
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854276

## Citation

> US National Institutes of Health, RePORTER application 10854276, Deciphering the Roles of STING-Mediated T cell Pyroptosis in Antitumor Immunity (1R37CA288747-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10854276. Licensed CC0.

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