Unlocking the Therapeutic Potential of the cGAS–STING Pathway through TREX1 Targeting

Given the limitations observed during the development of stimulator of IFN gene (STING) agonists, investigators have searched for alternative strategies to promote IFN signaling and augment antitumor immunity. Upstream pathways that promote the accumulation of cytosolic cyclic dinucleotides trigger STING activation, revealing a critical role for the three-prime repair exonuclease 1 (TREX1) enzyme, which serves to degrade cytosolic cyclic dinucleotides. In this issue of Cancer Research, Xing and colleagues describe the discovery and immunologic testing of a novel TREX1 inhibitor that augments IFN signaling in situ while promoting CD8+ T-cell immunity and suppressing tumor progression in preclinical tumor models. Utilizing an engineered inducible Trex1 knockout mouse model, the authors show that systemic TREX1 ablation in adult mice induces only modest inflammatory pathology. These studies demonstrate that systemic delivery of a small-molecule inhibitor of TREX1 enhances anti-PD-1 efficacy and suggest that TREX1 targeting may represent an effective strategy for activating the cyclic GMP-AMP synthase-STING pathway in future clinical trials. See related article by Xing et al., p. 2858.