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Characterization of a transmembrane-activating STING agonist using genetically humanized mice
Journal article   Open access   Peer reviewed

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

Nobuyo Mizuno, Jinu Abraham, Kevin Jimenez-Perez, Ian Rose, Laura Springgay, Dylan Boehm, Takeshi Ando, Daniel Streblow, Janine Ward, Shannon Miller, …
Cell reports (Cambridge), v 45(6), 117475
23 Jun 2026
DOI: https://doi.org/10.1016/j.celrep.2026.117475
PMID: 42228573
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https://doi.org/10.1016/j.celrep.2026.117475View
Published, Version of Record (VoR) Open

Abstract

adjuvant cancer innate immunity interferon vaccine
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. [Display omitted] •INI3069 is a human-selective STING agonist that functions through the transmembrane domain•A genetically humanized STING mouse model to characterize the in vivo effects of INI3069•INI3069 enhances both humoral responses to co-administered antigen and anti-tumor responses•INI3069 induces different molecular and immune effects compared to conventional STING agonists Mizuno et al. describe the synthesis of a human-selective STING agonist, INI3069, that activates conventional TBK1-mediated cellular processes such as IRF3 phosphorylation and ISG expression while blocking TBK1-independent phenotypes including TFEB activation, autophagy, and Golgi trafficking. Using genetically humanized STING mice, they find that INI3069 augments anti-tumor responses in vivo.

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