HER2-AKT1 Oncogenic Pathway In DNA Innate Immune Sensing And Anti-tumor Immunity

Sensing cytosolic DNA through the cGAS-STING pathway constitutes a widespread innate immune mechanism to sentinel damage and microbe invasion.Evading this cytosolic DNA surveillance is crucial in tumorigenesis but remains largely unexplored.Here we found that receptor tyrosine kinase HER2/ERBB2 potently inhibits cGAS-STING signaling and vitally prevents cells from senescence and apoptosis.HER2,but not related EGFR,associates strongly with STING and recruits AKT1 to STING signalosome.AKT1 directly phosphorylates TBK1 to prevent TBK1-STING association and K63-linked ubiquitination,thus inactivating STING signalosome.Unexpectedly,DNA sensing robustly activates the HER2-AKT1 axis,wiring a negative feedback.Accordingly,genetic or pharmacological targeting of HER2-AKT1 axis augments DNA sensing,antiviral host defense,and damage-induced cellular senescence and apoptosis,while activation of HER2 impedes STING-armed anti-tumor immunity in mice.Thus,our finding reveals a critical function of oncogenic pathway in innate immune sensing and unexpectedly connects HER2-AKT1 to cellular damage surveillance and anti-tumor immunity.