[R01] Novel endogenous and engineered activators of STING: from mechanisms to cancer therapy
Ente: National Cancer Institute
Scadenza: 2030-03-31
Importo max: 642.739 EUR
Paese: US
Descrizione
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.
Istituzione: UT SOUTHWESTERN MEDICAL CENTER
PI: Xiaochen Bai, Zhijian J Chen, Xuewu Zhang
Progetto: 5R01CA299257-02
Settori: National Cancer Institute
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