Unraveling sex-related cardiovascular toxicity of immune checkpoint inhibitors by pharmacovigilance and single-cell transcriptomic analysis.

[BACKGROUND] Immune checkpoint inhibitor (ICI) has revolutionized cancer treatment but can trigger severe immune-related adverse events (irAEs). Among these, cardiovascular irAEs (CV-irAEs) are rare yet associated with particularly high morbidity and mortality. This study aims to characterize the clinical features and underlying molecular mechanisms of CV-irAEs using pharmacovigilance and single-cell RNA sequencing data.

[METHODS] CV-irAEs are identified in the FDA Adverse Event Reporting System (FAERS) database through disproportionality analysis using reporting odds ratios. Onset times are compared across clinical variables using non-parametric tests. Factors associated with fatal outcomes are evaluated by Fisher's exact test, whereas logistic regression is employed to identify predictors of CV-irAEs occurrence. Finally, single-cell RNA sequencing explores sex differences in myocarditis irAEs.

[RESULTS] Twenty-six cardiovascular toxicity events are identified as CV-irAEs. Over 55 % of patients with CV-irAEs are diagnoses with lung or skin cancer. Additionally, CV-irAEs have a 43.91% fatality rate, and 51.82% of patients experience CV-irAEs within one month of ICI therapy initiation. Notably, patients over 75 years of age and those receiving anti-PD-1 monotherapy or combination therapy with anti-CTLA-4 are more susceptible to developing CV-irAEs. Furthermore, males experience more severe CV-irAEs. Accordingly, single-cell analysis reveals enhanced MIF and CD99 signaling between dendritic cells and effector memory T cells in male myocarditis irAEs patients, potentially explaining their greater susceptibility to severe CV-irAEs compared to females.

[CONCLUSIONS] We identify key clinical risk factors and a male-specific immune signature in CV-irAEs, providing a foundation for personalized risk assessment and further mechanistic studies.