The study investigates the role of innate DNA sensing through cyclic GMP-AMP synthase (cGAS) in regulating cellular senescence and the senescence-associated secretory phenotype (SASP). The authors find that cGAS recognizes cytosolic chromatin fragments (CCFs) in senescent cells, which triggers the production of SASP factors via the Stimulator of Interferon genes (STING) pathway, promoting paracrine senescence. They demonstrate that diverse stimuli of cellular senescence, including oxidative stress, oncogene signaling, irradiation, and pro-senescent drugs, engage the cGAS-STING pathway in vitro and in vivo. The deficiency of cGAS or STING results in an accelerated proliferation rate and compromised induction of senescence markers. The study also shows that cGAS-dependent regulation of senescence occurs upon irradiation and oncogene activation in vivo. These findings establish the cGAS-STING pathway as a crucial regulator of senescence and the SASP.The study investigates the role of innate DNA sensing through cyclic GMP-AMP synthase (cGAS) in regulating cellular senescence and the senescence-associated secretory phenotype (SASP). The authors find that cGAS recognizes cytosolic chromatin fragments (CCFs) in senescent cells, which triggers the production of SASP factors via the Stimulator of Interferon genes (STING) pathway, promoting paracrine senescence. They demonstrate that diverse stimuli of cellular senescence, including oxidative stress, oncogene signaling, irradiation, and pro-senescent drugs, engage the cGAS-STING pathway in vitro and in vivo. The deficiency of cGAS or STING results in an accelerated proliferation rate and compromised induction of senescence markers. The study also shows that cGAS-dependent regulation of senescence occurs upon irradiation and oncogene activation in vivo. These findings establish the cGAS-STING pathway as a crucial regulator of senescence and the SASP.