TREX1 , a predator for treating MSI ‐H tumors?

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.