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Objective and design <p>Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.</p> Material or subjects <p>We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.</p> Results <p>Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.</p> Conclusions <p>We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.</p>

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Mediation of macrophage M1 polarization dynamics change by ubiquitin-autophagy-pathway regulated NLRP3 inflammasomes in PD-1 inhibitor-related myocardial inflammatory injury

  • 期刊论文

  • 发表日期：

    2025年3月18日

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  • Yanxin Chen,
  • Yuxi Luo,
  • Yunwei Liu,
  • Xingpeng Qiu,
  • Daya Luo,
  • Anwen Liu

摘要

Objective and design

Immune checkpoint inhibitors (ICIs)-induced cardiac injury is a life-threatening immune-related adverse events (irAEs). However, the current understanding of its pathogenesis and therapeutic options is relatively limited. We aimed to provide a comprehensive overview of the myocardial inflammatory injury process and underlying mechanisms associated with ICIs.

Material or subjects

We conducted a descriptive analysis of lung cancer patients with ICIs-induced myocarditis at our institution and validated our clinical findings using single-cell sequencing (scRNA-seq) data. Furthermore, we established animal and cellular models to investigate the underlying mechanisms.

Results

Our findings revealed that lung cancer patients with ICIs-induced myocarditis exhibit an early increase in peripheral blood monocytes, which migrate to the heart and differentiate into macrophages, ultimately leading to myocardial inflammation. Mechanistically, programmed death-1 (PD-1) inhibition triggers myocardial inflammation through the activation of the signal transducer and activator of transcription 1 (STAT1)/nuclear factor kappa-B (NF-κB)/oligomerization domain (NOD)-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling pathway and drives the polarization of macrophages towards the M1 phenotype. However, the ubiquitin (Ub)-autophagy pathway degrades NLRP3 inflammasomes, resulting in the gradual resolution of inflammation and the transition of M1 macrophages to the M2 phenotype. Finally, mouse experiments confirmed that NLRP3 inhibition using MCC950 effectively alleviates myocardial inflammatory injury.

Conclusions

We recommend monitoring fluctuations in peripheral blood monocyte counts in lung cancer patients undergoing ICIs treatment. Additionally, MCC950 holds potential as a therapeutic agent for ICIs-induced cardiac inflammation injury.