Introduction: The Growing Challenge of ICI-Induced Cardiotoxicity
The landscape of oncology has been fundamentally transformed by the advent of immune checkpoint inhibitors (ICIs). By blocking inhibitory pathways such as programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), these therapies have significantly improved survival across various malignancies. However, the non-specific activation of the immune system often leads to immune-related adverse events (irAEs). Among these, ICI-induced myocarditis is particularly feared. Although it occurs in less than 1% of patients, it carries a high mortality rate—often exceeding 40% to 50%—and frequently presents as a fulminant clinical course characterized by arrhythmias, heart failure, and cardiogenic shock.
The therapeutic horizon has recently expanded with the introduction of relatlimab, a monoclonal antibody targeting lymphocyte-activation gene 3 (LAG-3). When combined with nivolumab (anti-PD-1), relatlimab has shown superior efficacy in treating advanced melanoma. However, this potent combination has also been associated with a higher incidence of myocarditis compared to PD-1 monotherapy. Despite the clinical urgency, the specific immunological drivers that cause T cells to infiltrate the myocardium under dual LAG-3/PD-1 blockade have remained poorly understood until now.
