# STING-dependent activation of Natural Killer cells by viral and tumor DNA

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $362,894

## Abstract

The cGAS-STING pathway senses cytosolic DNA in infected cells and cancer cells and triggers production of
type I interferon and other cytokines, thus eliciting immune responses. Deficiency in the pathway prevents T
cell responses to several viruses and to transplanted tumor lines. Our new results show that the pathway is
critical for activating spontaneous NK cell responses against cancer, and virus infections. Furthermore, in
probing the underlying mechanisms, our research has uncovered a new cellular mechanism whereby cGAS
and STING activate immune responses. Using genetic approaches, we found that the NK response to
transferred tumor cells depends on cGAS expression in tumor cells and STING expression in host cells. We
interpret these data to indicate that cGAS activation is the key event that occurs in infected or transformed cells
resulting in the production of the cyclic dinucleotide cGAMP. cGAMP is then transferred from the
infected/transformed cells to other immune cells, such as antigen presenting cells, which are induced to initiate
the immune response. Hence, we propose that cGAMP transfer between cells is a fundamental
mechanism in immune activation. In considering how cGAMP is transferred between cells, we hypothesized
that specific membrane transporters must play a role. Using a genome-wide CRISPRi screen, we identified a
transporter molecule that specifically imports cGAMP into cells. Using a series of knockout mice and
conditional knockout mice, and cellular manipulations and transfers, we propose to test the requirement of
cGAS-STING signaling in NK and T cell responses to cancer and DNA viruses, the generality of the
requirement of the transfer mechanism in viral infections and cancer models and for T cell and NK cell
responses, the roles of the newly identified transporters in the process, and to define the specific cells that
must import the cGAMP for immune responses to occur. Specifically, we will: (1) Determine the sites of
action of cGAMP and STING and intercellular transfer of cGAMP in anti-viral responses, including NK
and T cell responses; (2) Determine sites of action of cGAMP and STING and intercellular transfer of
cGAMP in T cell responses to cancer, in transfer models and GEM cancer models; (3) Determine roles of
cGAMP transporters in anti-viral and anti-tumor and immune responses. Using conditional knockout mice
and inhibitor studies, we will test their function in anti-herpesvirus and anti-tumor responses, including a GEM
model of cancer.

## Key facts

- **NIH application ID:** 9888196
- **Project number:** 2R01AI113041-06A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** DAVID H RAULET
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,894
- **Award type:** 2
- **Project period:** 2014-06-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888196

## Citation

> US National Institutes of Health, RePORTER application 9888196, STING-dependent activation of Natural Killer cells by viral and tumor DNA (2R01AI113041-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9888196. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*