Immune Mechanisms of Viral, Autoimmune, and Immune Checkpoint Inhibitor-Associated Myocarditis

Myocarditis and inflammatory cardiomyopathy are immune-mediated diseases of the heart with diverse infectious and noninfectious triggers and heterogeneous outcomes. Viral infection remains the main cause of myocarditis. Noninfectious forms include lymphocytic, eosinophilic, giant cell, cardiac sarcoidosis, and immune checkpoint inhibitor-associated myocarditis. Prognosis worsens with left ventricular dysfunction, heart failure, or malignant arrhythmias, yet the determinants of recovery versus progression to dilated cardiomyopathy (DCM) remain uncertain. This review integrates human studies with mechanistic models to map convergent pathways that connect pattern-recognition signaling, antigen presentation, and T- and B-cell responses with monocyte and macrophage networks that drive injury, fibrosis, and electrical instability. Across etiologies, α-myosin heavy chain (α-MyHC) reactive T cells recur as key effectors. We advance a unifying model in which cardiac tissue-resident memory T cells (TRMs) specific for myosin persist in health but ignite disease when tolerance is breached by infection, injury, or checkpoint blockade. We appraise coxsackievirus B3 (CVB3) infection, experimental autoimmune myocarditis (EAM), and checkpoint perturbation systems that capture patient heterogeneity and enable tracking of antigen-specific responses. Building on these insights, we outline priorities for biomarker-guided endotyping, imaging-omics integration, and targeted immunomodulation that limits progression to inflammatory cardiomyopathy while preserving protective tissue immunity and, in ICI settings, antitumor immunity.