# TREX1, a predator for treating MSI‐H tumors?

## TL;DR

TREX1 helps MSI-H tumors avoid immune detection by degrading DNA, and blocking it could improve immunotherapy responses.

## Contribution

The study identifies TREX1 as a novel target for enhancing immunotherapy in MSI-H tumors.

## Key findings

- TREX1 degrades cytosolic DNA and suppresses the cGAS–STING–IFN-I pathway in MSI-H tumors.
- Loss of TREX1 promotes immune cell infiltration and antitumor immunity.
- Targeting TREX1 could overcome resistance to immune checkpoint blockade.

## Abstract

Immunotherapy has revolutionized cancer treatment; yet, a subset of patients with microsatellite instability‐high (MSI‐H) tumors fails to respond to treatment despite their elevated tumor mutational burden and immunogenic potential. In a recent study, Xu et al. uncover a key mechanism of immune evasion in MSI‐H tumors mediated by the exonuclease TREX1, which degrades cytosolic DNA and suppresses activation of the cyclic GMP‐AMP synthase—stimulator of interferon genes (cGAS‐STING)—type I interferon pathway. Loss of TREX1 restores cytosolic DNA sensing, promotes CD8+ T and NK cell infiltration, and enhances antitumor immunity. These findings highlight TREX1 as a potential therapeutic target to overcome resistance to immune checkpoint blockade.

Immunotherapy benefits many patients; yet, some with MSI‐H tumors remain unresponsive despite their high immunogenicity. Xu et al. reveal that TREX1 enables immune evasion by degrading cytosolic DNA and suppressing cGAS–STING–IFN‐I signaling. TREX1 loss restores DNA sensing, increases CD8+ T and NK cell infiltration, and boosts antitumor immunity, highlighting TREX1 as a promising target to overcome immunotherapy resistance.