The Cardio-Onco-Immune Axis: immunopathological mechanisms in the cardiac microenvironment of checkpoint inhibitor-induced myocarditis.

Abstract

The use of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, greatly improving patient survival rates. However, immune-related adverse events (irAEs), particularly immune checkpoint inhibitor-induced myocarditis (ICI myocarditis), have emerged as major concerns. These events are often fatal and present complex clinical challenges. Employing the Cardio-Onco-Immune Axis framework, this review systematically integrates recent mechanistic advances with the epidemiology, clinical manifestations, diagnosis, and treatment strategies, organizing the pathogenesis into three chronological phases. Phase 1-tumor antigen priming-involves thymic escape of cardiac-specific T cells followed by tumor-driven expansion of this self-reactive repertoire. Phase 2-systemic immune disinhibition-is triggered by ICI therapy, which impairs regulatory T cell (Treg)-mediated suppression and releases checkpoint inhibition, converting the primed pool into activated effector T cells. Phase 3-cardiac microenvironmental amplification-is driven by a multicellular inflammatory network within the myocardium that converts limited inflammation into progressive, often fulminant myocardial injury. The review also outlines future research avenues aimed at improving diagnostic techniques, discovering new biomarkers, and developing targeted interventions for immune pathways. By elucidating the mechanisms behind ICI myocarditis, this review aims to lay the foundation for risk stratification models, facilitating earlier detection and more precise treatment.