Abstract 1767: Discovery of novel STING allosteric activators for targeted cancer immunotherapy

Abstract The Stimulator of Interferon Genes (STING) serves as a pivotal regulator of innate immunity, but the therapeutic modulation of this pathway poses a risk of triggering hyperimmune responses. To address this challenge, our study explores a natural STING agonist (cGAMP)-dependent STING allosteric activator as a potential solution. This novel allosteric activator demonstrates synergistic efficacy specifically under the low cGAMP conditions across various rodent and human cell lines. The compound induces structural modification in STING, enhancing its sensitivity to minimal cGAMP levels and thereby elevating type-1 interferon production. In vivo studies reveal that the compound enhances type I interferon induction, promotes a shift from innate to adaptive immune responses, and increases lymphocyte infiltration into tumors, leading to significant tumor regression with tumor-specific immune memory in a mouse model. In addition, co-administration with an immune check point inhibitor markedly enhances immuno-oncological efficacy. These findings underscore the potential of allosteric STING activators to expand the therapeutic index of cancer immunotherapy, offering new insights into the development of safer and more effective agents in cancer immunotherapy. Citation Format: Jeehee Lee, Eunsu Kim, Soo Yeon Baek, Wonjin Park, Jeeyoung Lee, Ye Seul Kim, Eunha Kim, Sanghee Lee. Discovery of novel STING allosteric activators for targeted cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1767.