Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies
A. Shamseddine, Suchit H. Patel, Valery Chávez, Zachary 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 Chan, Anthony F. Yu, Samuel F. Bakhoum, Adam M. Schmitt
Abstract
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.