The COX2-PGE2-PKA axis suppresses antiviral immunity by inhibiting mtDNA-dependent STING activation.

The stimulator of interferon genes (STING) pathway is essential for mounting robust innate immunity, yet its chronic activation can drive detrimental inflammation. Although multiple cell-autonomous mechanisms that restrain STING signaling have been reported, whether inflammatory mediators within the tissue microenvironment regulate STING activation remains elusive. Using herpes simplex virus type 1 infection as a model of STING activation, we revealed that the COX2-PGE2-PKA axis functions as a critical negative regulator of STING-mediated antiviral innate immunity. Mechanistically, PGE2 acts through the EP4-PKA cascade to induce PTEN-induced kinase 1 (PINK1)-mediated mitophagy by phosphorylating STOML2 at Ser29. This pathway facilitates the clearance of damaged mitochondria that serve as a source of immunostimulatory cytosolic mitochondrial DNA, thereby attenuating downstream STING activation and type I interferons while promoting viral replication. Together, these findings establish mitochondrial quality control as the mechanistic link between PGE2 signaling and mtDNA-dependent STING activation and identify the COX2-PGE2-PKA pathway as a druggable therapeutic target to enhance STING-mediated innate immunity.