# Inhibiting ADAR1‐Mediated Excessive Epigenetic A‐to‐I RNA Editing Improves the Immune Microenvironment and Increases Sensitivity to Immunotherapy in Lung Adenocarcinoma

## TL;DR

Inhibiting ADAR1 in lung adenocarcinoma improves the tumor immune environment and makes immunotherapy more effective.

## Contribution

This study shows ADAR1 inhibition enhances immunotherapy by improving immune cell infiltration and activating antitumor pathways.

## Key findings

- ADAR1 suppression increases PD-L1 and CD8+ T-cell infiltration in tumors.
- ADAR1 deficiency leads to dsRNA accumulation, activating RIG-I, MAVS, and IFN-β signaling.
- Reduced ADAR1 expression correlates with better immunotherapy responses in LUAD patients.

## Abstract

Adenosine‐to‐inosine (A‐to‐I) RNA editing, predominantly catalyzed by the enzyme adenosine deaminase acting on RNA 1 (ADAR1), has attracted interest due to its essential functions in regulating immune response and cancer progression. This research investigates ADAR1 inhibition as a promising strategy aimed at improving immunotherapy efficacy in lung adenocarcinoma (LUAD) and explores the underlying mechanisms. Findings from murine models demonstrate that ADAR1 suppression within tumors notably improves the immune microenvironment, marked by increased PD‐L1 expression and enhanced CD8+ T‐cell infiltration, as well as elevated levels of CXCL9, CXCL10, and CXCL11. These changes promote antitumor T‐cell immune responses and amplify the effects of immunotherapy. Mechanistic investigations further reveal that deficiency in ADAR1 leads to an increase in double‐stranded RNA (dsRNA), which serves as a substrate for A‐to‐I editing. This activates downstream signaling via dsRNA receptors, including RIG‐I and MAVS, thereby inducing the IFN‐β pathway. Significantly, IFN‐β contributes to the ADAR1‐dependent modulation of the tumor immune microenvironment and carcinogenesis in LUAD. Clinical validation in LUAD patients further confirms that reduced ADAR1 expression is associated with improved immunotherapy responses. These findings suggest inhibiting ADAR1‐mediated A‐to‐I RNA editing is a promising approach to enhance the efficacy of immunotherapy in LUAD.

This study investigated the potential of inhibiting ADAR1 which catalyzed excessive A‐to‐I RNA editing as a therapeutic strategy to augment the effectiveness of immunotherapy in LUAD. Mouse models demonstrated that inhibiting ADAR1 in tumor cells significantly improved the immune microenvironment by increasing PD‐L1 expression and CD8+ T‐cell infiltration, as well as increasing the levels of CXCL9, CXCL10, and CXCL11. Further, dsRNA accumulated more in ADAR1‐knockdown cells, activating RIG‐I, MAVS, and the subsequent IFN‐β signaling pathway. Graphical Abstract image was created with BioRender.com.