GPR17 modulators(Smith, Gambrell & Russell)

Three-prime repair exonuclease 1 (TREX1) is the major DNase in mammalian cells that degrades cytosolic DNA to prevent activation of the cGAS-STING pathway. Genotoxic stress, DNA damage, and radiotherapy induce TREX1 expression in cancer cells, allowing them to evade innate immune activation of type I interferon (IFN-I)-mediated antitumor response. Therefore, targeting TREX1 could represent a potential approach to stimulate antitumor immunity and enhance therapeutic efficacy. Here, we conducted a high-throughput small-molecule inhibitor (SMI) screen of TREX1 using a cell-free DNase assay. Compound 296 specifically inhibited TREX1 DNase activity at low micromolar concentrations, induced IFN-I signaling in cancer cells, and inhibited tumor growth in mice in an 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 blockade, demonstrating the feasibility of an immune-safe therapeutic window. Together, these data demonstrate the antitumor efficacy and immune safety of multiple therapeutic modalities, including targeting TREX1 using SMIs and employing TREX1 knockout tumor cells as an autologous cancer vaccine, which should pave the way for developing TREX1-targeted cancer immunotherapies.