Molecular Therapy: Nucleic Acids (Mar 2024)

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

Journal volume & issue
Vol. 35, no. 1
p. 102126

Abstract

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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.

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