Innate immune signaling drives late cardiac toxicity following DNA-damaging cancer therapies

Area of Science:

• Oncology
• Cardiology
• Immunology

Background:

• Late cardiac toxicity is a serious, often fatal, complication of cancer treatments.
• The underlying mechanisms of this cardiotoxicity are poorly understood, limiting treatment options.

Purpose of the Study:

• To elucidate the pathogenic mechanism of DNA damage-induced late cardiac toxicity.
• To identify potential therapeutic targets for mitigating cardiotoxicity.

Main Methods:

• Investigated the role of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) signaling in DNA damage-induced cardiotoxicity.
• Utilized mouse models with genetic ablation of cGAS-STING signaling.
• Administered a STING antagonist in conjunction with DNA-damaging therapies.

Main Results:

• DNA-damaging agents activate cGAS-STING-dependent type I interferon signaling, leading to delayed cardiac inflammation.
• Genetic deletion of cGAS-STING signaling prevented inflammation, cardiac dysfunction, and mortality in mice.
• STING antagonist treatment suppressed cardiac interferon signaling and reduced cardiotoxicity.

Conclusions:

• Activation of cGAS-STING-dependent type I interferon signaling is a key mechanism in DNA damage-induced late cardiac toxicity.
• Targeting the cGAS-STING pathway offers a promising therapeutic strategy to prevent and treat cardiotoxicity in cancer survivors.