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Characterization of a Novel Transmembrane Activating STING Agonist using Genetically Humanized Mice.

Nobuyo Mizuno¹, Jinu Abraham¹, Kevin Jimenez-Perez¹

¹Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America.

Biorxiv : the Preprint Server for Biology

|August 12, 2025

Summary

Researchers developed novel STING agonists and humanized mice for testing. The lead molecule, INI3069, shows promise as a vaccine adjuvant and cancer therapy by activating transmembrane STING signaling.

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Area of Science:

Immunology
Pharmacology
Molecular Biology

Background:

STING (STimulator of INterferon Genes) is a key pattern recognition receptor involved in innate immunity.
Pharmacologic STING agonists can enhance vaccine efficacy and antitumor responses, but clinical translation remains limited.
Distinct cellular responses are linked to cytosolic versus transmembrane STING activation, with limited tools for studying the latter in vivo.

Purpose of the Study:

To synthesize novel STING agonists effective against various STING protein variants.
To develop and validate a genetically humanized mouse model for in vivo testing of human-selective STING agonists.
To investigate the in vivo effects of transmembrane STING agonism using a novel agonist (INI3069).

Main Methods:

Synthesis of novel STING agonists targeting both allelic variants and transmembrane domains.
Generation of genetically humanized STING mice expressing human STING protein.
In vivo evaluation of the lead agonist INI3069 for its mechanism, immune effects, and therapeutic potential.

Main Results:

INI3069, a novel transmembrane STING agonist, was synthesized and demonstrated efficacy in humanized mice.
INI3069 exhibits distinct molecular and immune effects compared to conventional STING agonists.
INI3069 enhanced antibody responses to co-administered antigens and demonstrated antitumor efficacy.

Conclusions:

This study presents the first in vivo examination of transmembrane STING agonism.
INI3069 represents a potential novel vaccine adjuvant and oncological therapeutic.
The developed humanized mouse model is suitable for evaluating human-selective STING agonists in vivo.