Characterization of a transmembrane-activating STING agonist using genetically humanized mice

Summary Stimulator of interferon genes (STING) is a pattern recognition receptor that activates type I interferon and proinflammatory responses following cytosolic DNA exposure. Its pharmacologic stimulation enhances vaccine potency and generates anti-tumor responses, but clinical trials evaluating STING agonists have not supported human use. STING activation can occur through the engagement of cytosolic or transmembrane protein domains, processes to which distinct phenotypes are attributed. However, transmembrane agonists are human selective, and conventional in vivo testing is not feasible. We synthesized human-selective STING agonists and describe genetically humanized STING mice as an in vivo model useful for examining these agonists. Experiments suggest that the lead molecule functions through binding to the STING transmembrane region, and its comparison with conventional agonists reveals differences in molecular and immune effects. This work both represents a thorough in vivo immune characterization of the effects of transmembrane STING agonism and demonstrates the efficacy of a potential vaccine adjuvant and oncological therapeutic.