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

作者：Cong Xing, Xintao Tu, Wanwan Huai, Zhen Tang, Kun Song, Devon Jeltema, Kennady Knox, Nicole Dobbs, Kun Yang, Nan Yan · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/0008-5472.can-24-2747 · 被引用次数：19 · 研究领域：interferon and immune responses、Inflammasome and immune disorders、Cytokine Signaling Pathways and Interactions

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 alpha/beta receptor (IFNAR)-dependent manner. Treatment with compound 296 also stimulated T-cell infiltration into tumors and synergized with immune checkpoint blockade. Trex1 knockout cancer cells elicited robust systemic antitumor immunity through tumor-intrinsic cGAS-STING activation and functioned as autologous cancer vaccines that protected against tumor challenge and metastasis. An inducible whole-body Trex1 knockout mouse model was established to simulate "on-demand" systemic TREX1 inactivation in adult mice. Sustained TREX1 loss suppressed a broad range of solid and metastatic tumors in adult mice without incurring severe immune toxicity, even when combined with immune checkpoint blocka...