Cardiac tertiary immune niches drive immune activation in immune checkpoint inhibitor myocarditis

Immune checkpoint inhibitor (ICI) myocarditis is a rare but frequently fatal immune-related adverse event of cancer immunotherapy. Understanding the mechanisms of this toxicity is critical to balancing treatment with maintenance of antitumor immunity. Using integrated spatial and single-cell analyses in a pharmacological murine model, we identified regional infiltration of Ly6C⁺ monocytes and PD-1⁺ CD8⁺ T cells in the heart that organize into fibroblast-rich immune structures, which we term tertiary T cell niches (TTCNs). TTCNs serve as hubs for T cell activation, sharing features of tertiary lymphoid structures. A TTCN gene signature was strongly enriched in cardiac tissue from patients with ICI myocarditis. Complementary T cell receptor analyses revealed clonal expansion of cardiac T cells following ICI treatment. We further identified TTCN-associated cytokines and structural proteins as candidate therapeutic targets to reduce myocardial inflammation while considering tumor control. Together, these findings suggest that cardiac tertiary immune structures play a central role in ICI myocarditis and highlight pathways that could mitigate ICI cardiotoxicity.