NLRC4 Disrupts STING Signaling and Suppresses Antiviral Defense and Antitumor Immunity

STING plays a key role in innate immune sensing of cytosolic DNA, activating the TBK1/IRF3 signaling pathway to initiate an antiviral and antitumor immune response. Elucidating the STING activation mechanism is of great importance for immune surveillance. However, the exact mechanism of STING activation remains poorly understood. Here, we identify NLRC4 as a negative regulator of STING signaling. NLRC4 −/− mice exhibit heightened antiviral responses upon challenge with HSV‐1, and the loss of NLRC4 enhances phosphorylation of TBK1 and IRF3, leading to increased IFN production in bone marrow–derived macrophages (BMDMs) following stimulation with cytosolic DNA or a STING agonist. Mechanistic investigations reveal that NLRC4 directly interacts with the C‐terminal domain of STING. This interaction competitively disrupts STING association with STEEP, inhibiting STING trafficking at the ER exit. Furthermore, using the constitutively active STING mutant R281Q independent of 2′3′‐cGAMP binding, we found that NLRC4 impeded the recruitment of TBK1 and IRF3 to STING, thereby suppressing STING‐mediated antitumor immunity. Together, these data provide compelling evidence that NLRC4 negatively regulates STING activation and offer potential therapeutic targets for immune modulation.