Targeting Innate Immune Checkpoint TREX1 Is a Safe and Effective Immunotherapeutic Strategy in Cancer.

ABSTRACT: Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I IFN-mediated antitumor response. Therefore, targeting TREX1 could represent a potential approach to stimulate antitumor immunity. In this study, we conducted a high-throughput small-molecule inhibitor screen of TREX1 using a cell-free DNase assay. Compound 296 specifically inhibited TREX1 DNase activity at low micromolar concentrations, induced type I IFN signaling in cancer cells, and inhibited tumor growth in mice in an inteferon alp

SUBMITTER: Xing C 

PROVIDER: S-EPMC12316550 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature