# Targeting cellular double-stranded RNA homeostasis in breast cancer

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2021 · $373,774

## Abstract

Summary/Abstract
The immunologically inactive (cold) tumor is a major challenge for effective immunotherapies in many cancers,
including breast cancer. Increasing evidence has demonstrated that human cells express various types of
endogenous double-stranded RNAs (dsRNAs) regardless of pathogen invasion, and aberrant accumulation of
cellular dsRNAs could trigger a detrimental innate immune response in cells. In cancer, these endogenous
immunogenic dsRNAs are suggested as a source of immune induction to increase tumor response to
immunotherapy. However, to exploit the cellular dsRNAs in immunotherapy for cancer, we need to understand
the molecular mechanism for cellular dsRNA homeostasis in normal and malignant cells and find the specific
ways to modulate immunogenic dsRNAs. We found that inhibition of DEAD-box RNA helicase 3X (DDX3X)
resulted in the cytoplasmic accumulation of endogenous dsRNAs in the breast cancer cells. Loss of DDX3X
increased the type I interferon production, STAT1 activation, IFN-stimulated genes (ISGs) expression, and the
MHC class I expression with the enhanced antigen presentation on the breast cancer cells. DDX3X inhibition
also suppressed the tumor growth and increased the tumor infiltration of active CD8+ T cells and DC in the
syngeneic breast cancer mouse model. We hypothesize that inhibiting DDX3X leads to aberrant accumulation
of endogenous dsRNAs, which triggers type I IFN responses and induces an innate immune response in the
tumor. The proposed studies will be focused on understanding the molecular mechanism by which DDX3X
regulates cellular dsRNA homeostasis, providing a link between cellular dsRNAs and immune signals in breast
cancer cells, and establishing novel immunotherapeutic strategies for breast cancer. In Aim 1, we will
determine the molecular mechanism by which DDX3X regulates cellular dsRNAs; In Aim 2, we will study
DDX3X-dsRNAs-Type I IFN axis in cancer cells and human tumor; In Aim 3, we will explore the effect of
inhibiting DDX3X to increase anti-tumor immunity and sensitize tumors to immunotherapy. Our study will reveal
a novel regulatory mechanism of endogenous dsRNAs in cancer and may lead to novel therapeutics targeting
DDX3X for new combinatory immunotherapy.

## Key facts

- **NIH application ID:** 10278680
- **Project number:** 1R01CA262418-01
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Cecil Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,774
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10278680

## Citation

> US National Institutes of Health, RePORTER application 10278680, Targeting cellular double-stranded RNA homeostasis in breast cancer (1R01CA262418-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10278680. Licensed CC0.

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