# Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $718,598

## Abstract

Project Summary/Abstract
Checkpoint blockade has revolutionized the field of cancer immunotherapy treatment, but many tumors remain
unresponsive due to lack of effector T cell infiltration and activation in the tumor microenvironment. Innate
immune priming of these “cold” tumors has emerged as a therapeutic strategy for increasing the efficacy of
checkpoint blockade through stimulated type I interferon (IFN) production and downstream adaptive response.
Recent efforts and ongoing clinical trials have focused on activation of the STING-dependent antiviral pathway
to promote IFN production in the tumor microenvironment. However, many tumors downregulate STING
signaling, and the therapeutic effects of STING agonists are thought to be mediated by their effects on tumor-
infiltrating host myeloid cells.
 Our lab recently discovered that the DNA damage sensor DNA-PK triggers a STING-independent DNA
sensing pathway (SIDSP) in human cells that potently activates IFN production in response to foreign DNA.
We have developed synthetic superagonists of DNA-PK-dependent antiviral immunity that trigger potent
antiviral responses in human melanoma cells that are unresponsive to STING agonists. We hypothesize that
activation of the SIDSP within tumor cells will provide a unique signal to enhance inflammation within tumors
and will stimulate potent immune responses.
 The goal of this proposal is to assess DNA-PK-SIDSP activation as a therapeutic strategy in human
cancer. We will determine how DNA-PK directs distinct outcomes to DNA damage versus foreign DNA, and we
will evaluate the therapeutic potential of triggering the DNA-PK-SIDSP in human tumors, in vitro and in vivo
using cutting edge humanized mouse models. Our studies will uncover fundamental new aspects of the biology
of the SIDSP, together with the first pre-clinical evaluation of DNA-PK activation as a novel cancer
immunotherapy.

## Key facts

- **NIH application ID:** 10364056
- **Project number:** 1R01CA258606-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** ANTHONY RONGVAUX
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $718,598
- **Award type:** 1
- **Project period:** 2022-01-20 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364056

## Citation

> US National Institutes of Health, RePORTER application 10364056, Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy (1R01CA258606-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364056. Licensed CC0.

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