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Immune Checkpoint Inhibitor-Induced Myocarditis: A Deeper Dive

Inflammatory Mechanisms Unraveled

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but their use can lead to immune-related adverse events, including myocarditis. Researchers at the forefront of immunological research have recently uncovered the intricate mechanisms underlying ICI-induced myocarditis.

Gasdermin-E: A Key Culprit

Gasdermin-E (GSDME), a protein previously associated with cell death, has emerged as a pivotal player in ICI-induced myocarditis. Upon ICI treatment, GSDME undergoes a conformational change, triggering pyroptosis, a form of inflammatory cell death.

The cGAS-STING-IFNβ Axis Activated

Pyroptosis leads to the release of DNA fragments into the cytosol, where they are detected by cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor. cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP), a second messenger that binds to the stimulator of interferon genes (STING). This interaction triggers the production of type I interferons (IFNs), particularly IFNβ.

Intensified Immune Inflammation

IFNβ plays a critical role in activating immune responses. It enhances the expression of MHC class I molecules on cardiomyocytes, making them more susceptible to immune attack. Additionally, IFNβ recruits immune cells, including cytotoxic T cells and natural killer (NK) cells, to the heart, exacerbating the inflammatory response and leading to myocarditis.

Conclusion

The discovery of GSDME's involvement in ICI-induced myocarditis and the subsequent activation of the cGAS-STING-IFNβ axis provides valuable insights into the pathogenesis of this immune-related adverse event. Understanding these mechanisms can help guide the development of novel therapeutic strategies to mitigate myocarditis risk while preserving the antitumor efficacy of ICIs.