Integrated multi-omics identifies distinct immune signatures with diagnostic and therapeutic implications in immune checkpoint inhibitor-induced myocarditis

Abstract Immune checkpoint inhibitor-associated myocarditis (ICI-myocarditis) is a rare but frequently fatal immune-related adverse event. A comprehensive understanding of the cellular and molecular determinants driving ICI-myocarditis is essential for improving diagnostic precision and developing targeted interventions. We delineate the immune landscape of ICI-myocarditis via scRNA-seq, flow cytometry, Olink proteomics, and multiplex cytokine profiling. We demonstrate that high levels of baseline ISG15⁺CD8⁺ T cells are linked to the proinflammatory features of monocytes and in vitro experiments confirm the existence of circulating ISG15⁺CD8⁺ T cells with a high potential to induce cardiomyocyte apoptosis, supporting their pathogenic potential for cardiomyocyte cytotoxicity. Notably, intercellular crosstalk between these subsets is possibly mediated via the CCL2-CCR2 axis, and its blockade attenuated ICI-induced cardiac injury in vivo. Based on the inflammatory signature in ICI-myocarditis, we develop an 8-protein custom panel with promising performance in distinguishing ICI-myocarditis from other ICIs-treated controls. JAK-STAT pathway activation promotes inflammatory programs in both ISG15⁺CD8⁺ T cells and monocytes. Furthermore, JAK-STAT inhibition ameliorates cardiac dysfunction and inflammatory infiltration while enhancing the response to anti-PD-1 therapy in mouse models. In summary, this study implicates immune-pathogenic features of ICI-myocarditis and provides a possible basis for future therapies.