Novel endogenous and engineered activators of STING: from mechanisms to cancer therapy

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

STING is an ER-associated membrane innate immune protein vital for cancer defense. Despite promising preclinical results, STING agonists have not shown significant success in early clinical trials due to complex signaling, transient activation as a result lysosomal degradation, and detrimental side-effects on healthy tissues. The first Aim of this project is to understand novel lipid-dependent activation and regulatory mechanisms of STING, guiding the development of improved STING-targeting cancer therapies. Our previous research identified PSC7A, a polymer that form nanoparticles that not only can efficiently deliver STING agonists to cells but also can directly bind and activate STING on their own. The PSC7A-activated STING avoids lysosomal degradation seen with the endogenous ligand cGAMP, thereby exhibiting prolonged STING activation and type-I interferon expression, leading to improved antitumor efficacy. The second Aim of this project is to apply cryo-EM to dissect the molecular mechanism underlying PSC7A- induced STING activation. In the third Aim, we will test PSC7A nanoparticles loaded with cGAMP, STING agonists, and specific lipids in various animal tumor models to evaluate their synergistic antitumor effects. Ultimately, this research will facilitate the design of the next-generation STING agonists that precisely control immune signaling, with maximal antitumor immunity but minimal systematic immune-related toxicity in healthy tissues.