Abstract 6598: Inhibition of cGAS as a strategy to restore anti-tumor immunity response to STING agonist in chromosomally unstable tumors

Abstract The activation of STING (stimulator of interferon genes) has been widely shown to induce signaling pathways, triggering type I interferon and ultimately generating anti-tumor immunity. Whereas initial preclinical studies on STING agonists exhibited boost in anti-tumor response, clinical trials combining STING agonist and immune checkpoint blockade agent PD-1 reported that only small subset of patients benefited from the treatment. This study highlights a potential key mechanism underlying the lack of benefit from STING agonist observed in most clinical trial patients. We reveal a phenomenon known as chromosomal instability (CIN), characterized by persistent chromosome segregation errors over multiple rounds of mitosis, drives chronic activation of cGAS (cyclic GMP‒AMP synthase) through continuously supplying its substrate in the form of micronuclei. Chronic activation of cGAS stimulates degradation of its downstream target STING in a feedback-loop manner. This consequently attenuates type I interferon signaling upon STING activation, blunting its anti-tumor response. Remarkably, we show suppression of CIN, achieved through introduction of mitotic centromere-associated kinesin (MCAK), or inhibition of cGAS activity, either by pharmacological agent or total genetic ablation of cGAS using CRISPR-Cas9, restores type I interferon production and anti-tumor immunity upon the administration of STING agonist, MSA-2 in four of the five advanced tumor models. Furthermore, we show this restoration of type I interferon signaling and anti-tumor immunity is cancer cell STING-dependent as genetic deletion of STING in the tumor cells nullifies this effect. In summary, we provide a mechanistic insight underlying the limited anti-tumor response observed in STING agonist trials and propose potential strategies, through finetuning of CIN level or inhibition of cGAS activity, to illicit stronger anti-tumor immunity in combination with STING agonist treatment. Citation Format: Christy Hong, Lindsay Caprio, Mercedes Duran, Meri Rogava, Hsiang-His Ling, Sreeharsha Gurrapu, Leon Ebel, Melody Di Bona, Benjamin Izar, Samuel F. Bakhoum. Inhibition of cGAS as a strategy to restore anti-tumor immunity response to STING agonist in chromosomally unstable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6598.