DNA-PKcs and PARP1 at the interface between DNA damage responses and cGAS–STING signaling: context-dependent roles and therapeutic implications

AIMS: To explore the roles of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and poly(ADP-ribose) polymerase 1 (PARP1) in both the DNA damage repair (DDR) pathway and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway mediated immune response, and to analyze the therapeutic potential of their inhibitors. METHODS: This is a review article synthesizing recent findings on the functions of DNA-PKcs and PARP1 in DDR, their context-dependent effects on the cGAS-STING pathway and the therapeutic mechanisms of their inhibitors. RESULTS: DNA-PKcs and PARP1 are key components of two major DDR mechanisms. Beyond their canonical repair functions, both factors significantly regulate the cGAS-STING pathway, a central mediator linking cytoplasmic DNA and the type I interferon response. CONCLUSION: DNA-PKcs and PARP1 connect genome maintenance with innate immune signaling through context-dependent mechanisms. Targeting these proteins represents a promising strategy for modulating cGAS-STING signaling and improving disease treatment.