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Here we report DNA-damaging agents such as radiation and anthracycline chemotherapies inducing delayed cardiac inflammation following therapy due to activation of cGAS- and STING-dependent type I interferon signaling. Genetic ablation of cGAS\u2013STING signaling in mice inhibits DNA damage\u2013induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA-damaging therapies and effectively mitigates cardiac toxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.<\/jats:p>","DOI":"10.1084\/jem.20220809","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T02:53:24Z","timestamp":1669172004000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3686-5850","authenticated-orcid":true,"given":"Achraf","family":"Shamseddine","sequence":"first","affiliation":[{"name":"Division of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 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