# Targeting ATM to boost systemic effects of radiotherapy and immunotherapy

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $500,236

## Abstract

PROJECT SUMMARY
Immune checkpoint blockade (ICB) therapy has shown great promise in cancer treatment recently.
However, currently only a minority of patients could benefit from immune checkpoint therapy.
Although the molecular mechanisms involved in the differential responses of cancer patients to
immune checkpoint therapy remain unclear, a general consensus is that tumors with high
mutational burden or tumors with inflammatory phenotypes are more likely to respond to immune
checkpoint therapy due to the presence of higher numbers of anti-tumor T-cells. Thus it appears
that the main challenge to improve immune checkpoint therapy is to manipulate the tumor
microenvironment so it changes from a “cold” one with few anti-tumor T cells to a “hot” one with
many anti-tumor T cells. As such methods and agents that can increase the inflammatory
“hotness” of the tumor microenvironment are highly sought after. On the other hand, radiotherapy,
which has been used to treat localized tumors, has been recently shown to activate immune
signaling pathways. Those discoveries raise the tantalizing possibility that the efficacy of
radiotherapy may be enhanced by manipulating the tumor immune microenvironment.
In this project, we will examine the hypothesis that ATM inhibition is an effective approach to
activate the cGAS/STING pathway by down-regulating mitochondria biogenesis to enable ICB therapy
and boosts abscopal effect of radiotherapy.
We will initially conduct experiments to determine if ATM inhibition could significantly enhance
ICB therapy by use of CRISPR-mediated gene knockout of ATM (Aim 1). We will also attempt to
define the downstream molecular mechanisms and factors that are involved ATM inhibition-
mediated enhancement of ICB therapy (Aim 2). In addition, we will evaluate if a small molecule
inhibitor of ATM could enhance ICB therapy and the systemic (i.e. abscopal) effects of
radiotherapy in syngeneic mouse tumor models (Aim 3).
Upon completion of the project, we hope we can gain significant insights into the roles of ATM in
restraining activation of cellular innate immunity. Such understanding may facilitate the rapid
development of novel approaches to enhance ICB therapy and radiotherapy.

## Key facts

- **NIH application ID:** 10845286
- **Project number:** 5R01CA251439-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Fang Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $500,236
- **Award type:** 5
- **Project period:** 2021-03-09 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845286

## Citation

> US National Institutes of Health, RePORTER application 10845286, Targeting ATM to boost systemic effects of radiotherapy and immunotherapy (5R01CA251439-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10845286. Licensed CC0.

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