Engineering cGAS-agonistic oligonucleotides as therapeutics for cancer immunotherapy

Shurong Zhou; Ting Su; Furong Cheng; Janet Cole; Xiang Liu; Bei Zhang; Shaheer Alam; Jinze Liu; Guizhi Zhu

doi:10.1016/j.omtn.2024.102126

Engineering cGAS-agonistic oligonucleotides as therapeutics for cancer immunotherapy

Mol Ther Nucleic Acids. 2024 Jan 24;35(1):102126. doi: 10.1016/j.omtn.2024.102126. eCollection 2024 Mar 12.

Authors

Shurong Zhou^{1

2}, Ting Su², Furong Cheng², Janet Cole², Xiang Liu^{1

2}, Bei Zhang³, Shaheer Alam², Jinze Liu³, Guizhi Zhu^{1

4}

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Pharmaceutics and Center for Pharmaceutical Engineering and Sciences, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
³ Department of Biostatistics, School of Medicine, Bioinformatics Shared Resource, Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁴ Biointerfaces Institute, The Developmental Therapeutics Program, Rogel Cancer Center, Center for RNA Biomedicine, MI-AORTA Program, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I) responses. Yet, current approaches to cGAS-STING activation rely on STING agonists, which suffer from difficult formulation, poor pharmacokinetics, and marginal clinical therapeutic efficacy. Here, we report nature-inspired oligonucleotide, Svg3, as a cGAS agonist for cGAS-STING activation in tumor combination immunotherapy. The hairpin-shaped Svg3 strongly binds to cGAS and enhances phase separation to form Svg3-cGAS liquid-like droplets. This results in cGAS-specific immunoactivation and robust IFN-I responses. Remarkably, Svg3 outperforms several state-of-the-art STING agonists in murine and human cells/tissues. Nanoparticle-delivered Svg3 reduces tumor immunosuppression and potentiates immune checkpoint blockade therapeutic efficacy of multiple syngeneic tumor models in wild-type mice, but in neither cGas^-/- nor Sting^-/- mice. Overall, these results demonstrate the great potential of Svg3 as a cGAS agonistic oligonucleotide for cancer combination immunotherapy.

Keywords: MT: Novel therapeutic targets and biomarker development Special Issue; cGAS; cancer vaccines; combination immunotherapy; immunostimulants; oligonucleotide therapeutics.

Abstract

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