Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. 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–STING signaling in mice inhibits DNA damage–induced 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.
Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies
Disclosures: J.E. Liu reported consulting for Pfizer and Caption Health, honoraria from Philips, and Data and Safety Monitoring Board for Caelum Biosciences. N.D. Socci reported grants from National Institutes of Health during the conduct of the study. S.F. Bakhoum reported personal fees from Volastra Therapeutics Inc. and Sanofi and other support from Cancer Research UK and Prostate Cancer Foundation outside the submitted work; in addition, S.F. Bakhoum has a patent for targeting chromosomal instability and downstream cytosolic DNA signaling for cancer treatment licensed to Volastra Therapeutics Inc. and a patent for methods and strategies to target cytosolic dsDNA signaling in chromosomally unstable cancers pending. A.M. Schmitt reported spouse is an employee of Regeneron Pharmaceuticals. No other disclosures were reported.
S. Patel's current affiliation is Department of Radiation Oncology, Renown Regional Medical Center, Reno, NV, USA.
- Award Id(s): W81XWH1910002
- Award Id(s): R35 GM 124909
- Award Id(s): P30 CA 008748
Achraf Shamseddine, Suchit H. Patel, Valery Chavez, Zachary R. Moore, Mutayyaba Adnan, Melody Di Bona, Jun Li, Chau T. Dang, Lakshmi V. Ramanathan, Kevin C. Oeffinger, Jennifer E. Liu, Richard M. Steingart, Alessandra Piersigilli, Nicholas D. Socci, Angel T. Chan, Anthony F. Yu, Samuel F. Bakhoum, Adam M. Schmitt; Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies. J Exp Med 6 March 2023; 220 (3): e20220809. doi: https://doi.org/10.1084/jem.20220809
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