Cryo-electron microscopy revealed how phosphatidylinositol 4-phosphate (PI4P) and the experimental compound GNE-6468 work together to activate STING, a crucial immune signaling protein. The chemical agonist binds to a specific pocket in STING's transmembrane domain, triggering outward movement of the TM3 helix while PI4P provides complementary activation signals, collectively promoting protein oligomerization and downstream immune responses.
This mechanistic discovery advances our understanding of innate immunity beyond the well-known cGAS-STING pathway. Previous research established that STING activation requires Golgi translocation, but the precise molecular choreography remained mysterious. The dual-ligand activation model suggests that effective STING-based immunotherapies may need to target multiple binding sites simultaneously rather than relying on single agonists. This has immediate implications for cancer immunotherapy and autoimmune disease treatment, where STING modulation shows promise but current approaches lack precision. The structural insights could accelerate development of more potent STING modulators, though translating these molecular mechanisms into clinical applications will require extensive safety testing given STING's central role in inflammatory responses.