Suppression of antiviral innate immunity by the COX2-PGE2-PKA signaling axis by inhibiting the cytosolic mtDNA-dependent activation of STING

The innate immune cGAS-STING pathway is activated by cytosolic doubled-stranded DNA (dsDNA) to induce type I interferon response, which is essential for antiviral and antitumor immunity. However, intrinsic STING activation during viral infection or within the tumor microenvironment is often insufficient to achieve complete viral clearance or tumor regression, indicating the presence of additional mechanisms that evades its activity. Here, we identified COX2/PGE2 as an intrinsic negative regulator of STING activation, particularly in response to cytosolic mitochondrial DNA (mtDNA) generated during HSV-1 infection. Mechanistically, we demonstrated that PGE2 signals through the EP4-PKA axis to induce mitophagy and facilitate the clearance of immunostimulatory cytosolic mtDNA, thereby dampening STING-mediated antiviral response. Furthermore, we discovered STOML2 as a direct downstream target of PKA, thereby linking mitochondrial quality control to innate immune signaling. Together, our findings established the COX2/PGE2/PKA axis as an intrinsic negative regulator of STING signaling, which may be targeted to potentiate STING-mediated antiviral and antitumor immunity.