Cardiovascular toxicity from immune checkpoint inhibitor therapy: an inflammatory continuum

Immune checkpoint inhibitor (ICI) therapy has markedly improved outcomes in advanced malignancies but has also revealed a distinct spectrum of cardiovascular immune-related adverse events. Myocarditis represents the most severe manifestation, while non-inflammatory left ventricular dysfunction and vascular inflammation have emerged as additional phenotypes. Current evidence indicates that loss of immune checkpoint signalling disrupts cardiac immune tolerance, unleashing cytotoxic T-cell and macrophage responses that cause myocardial injury. Checkpoint inhibition expands pre-existing autoreactive memory T-cell pools that recognise cardiac autoantigens such as α-myosin, thereby lowering the threshold for recurrent or sustained immune activation. Mitochondrial damage activates cellular stress pathways that drive interferon-mediated inflammation, linking cellular stress to innate immune signalling. Paralleling myocardial effect, ICI therapy also promotes endothelial dysfunction and accelerates atherogenesis via local pro-inflammatory effects, thus increasing the risk of cardiovascular adverse events. Early detection through biomarker surveillance and advanced imaging, together with targeted immunomodulation, offers new opportunities for improved outcomes. Yet balancing cardiac safety with the maintenance of anti-cancer efficacy introduces a therapeutic dilemma that is only beginning to be defined. Here, we outline current insights into the mechanisms, manifestations and clinical challenges of ICI-related cardiovascular toxicity.