Cardiovascular toxicity induced by immune checkpoint inhibitors: mechanisms linking immune dysregulation and myocardial fibrosis.

Immune checkpoint inhibitors (ICIs) play a key role in cancer immunotherapy, enhancing outcomes for patients with multiple malignancies by blocking the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways. Nevertheless, their application is limited due to immune-related adverse events (irAEs), which comprise various manifestations, among which cardiovascular toxicities - primarily myocarditis, arrhythmias, pericarditis, and heart failure - are a major clinical challenge. While relatively rare, myocarditis has a fatality rate as high as 50%. The mechanisms underlying ICI-induced cardiovascular toxicity remain not fully understood, especially regarding how immune dysregulation translates into myocardial fibrosis. Herein, the immune dysregulation-inflammation-fibrosis axis is reviewed, and the mechanisms by which immune checkpoint blockade breaks cardiac immune tolerance, inducing T-cell activation, cytokine storms, and the subsequent production of anti-cardiac antibodies, are discussed. Moreover, the important function of non-coding RNAs (ncRNAs) in immunomodulatory and fibrotic pathways is then revealed as a key player in ICI-associated cardiac injury. It also discusses therapeutic strategies involving immune modulation and anti-fibrotic mechanisms, which may be suitable to reduce cardiovascular toxicity as well as improve the overall prognosis of patients. An improved mechanistic understanding underlying these processes will offer new theoretical insights into how to most effectively utilize ICIs safely.