Reactivating cGAS–STING Signaling by Targeting SOS1 Enhances Antitumor Immunity in NRAS -Mutant Tumors

Abstract NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type (WT) tumors, current therapies for NRAS-mutant cancers are limited. In this study, analysis of RNA sequencing data revealed a downregulation of the type I IFN response in NRAS-mutant tumors compared with NRAS WT tumors, which was associated with poor prognosis in NRAS-mutant melanoma. Knockdown of mutant NRAS, but not WT NRAS, enhanced the activation of cyclic GMP-AMP synthase (cGAS)–STING signaling. The formation of a trimeric complex between TBK1, STING, and IFN regulatory factor 3, which is required for the activation and nuclear translocation, was blocked in NRAS-mutant tumor cells. Inactivation of innate immune signaling by mutant NRAS altered cytokine production, resulting in cell autonomous and non–cell autonomous signaling to prevent tumor cell death and in evasion of tumor-immune surveillance. Screening of drugs for the ability to stimulate the release of CXCL10 revealed that SOS1 inhibitors reactivated cGAS–STING signaling in NRAS-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS–STING signaling and elicited an increased antitumor immune response in vitro and in vivo. Overall, this study provides insights into the regulation of antitumor immunity by mutant NRAS and uncovers a potential strategy for treating NRAS-mutant cancer. Significance: Suppression of innate immune signaling in NRAS-mutant tumors results from downregulation of the cGAS–STING axis and can be reversed using SOS1 inhibitors combined with STING agonists to restrain NRAS-mutant tumor growth.