| First Author | Zhou S | Year | 2024 |
| Journal | Mol Ther Nucleic Acids | Volume | 35 |
| Issue | 1 | Pages | 102126 |
| PubMed ID | 38352859 | Mgi Jnum | J:345622 |
| Mgi Id | MGI:7610132 | Doi | 10.1016/j.omtn.2024.102126 |
| Citation | Zhou S, et al. (2024) Engineering cGAS-agonistic oligonucleotides as therapeutics for cancer immunotherapy. Mol Ther Nucleic Acids 35(1):102126 |
| abstractText | 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. |
