Immune Profiling Identifies Inflammatory Signatures in Immune Checkpoint Inhibitor–Related Myocarditis

BACKGROUND: Immune checkpoint inhibitor-associated myocarditis (ICI-My) is rare but potentially life-threatening. Biomarkers that distinguish myocarditis-related inflammation from background immune activation induced by ICIs remain needed. OBJECTIVES: This study sought to define the circulating inflammatory and cellular immune landscape of ICI-My, relate these findings to clinical severity, and explore the feasibility of interleukin-6 receptor (IL-6R) blockade in selected steroid-refractory cases. METHODS: In this single-center retrospective cohort (January 2018 to June 2024), we performed biomarker profiling including multiplex cytokine profiling in 33 patients with ICI-My (7 severe and 26 nonsevere, 28 cytokines profiles) and 68 ICI-treated patients without myocarditis or other immune-related adverse events. Mass cytometry analyses compared 16 patients with ICI-My with 72 ICI-treated patients without myocarditis or other immune-related adverse events. We also describe eight steroid-refractory patients treated with tocilizumab on a compassionate-use basis. RESULTS: memory B- and T-cell populations, contraction of switched and unswitched memory B-cell compartments, and lower CXCR3 expression across memory T-cell subsets. No clear systemic complement activation signal was observed. High-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, aspartate aminotransferase, and alanine aminotransferase discriminated severe from nonsevere myocarditis more consistently than individual cytokines. In eight steroid-refractory cases, tocilizumab administration was feasible, but this uncontrolled series cannot establish efficacy. CONCLUSIONS: Peripheral immune profiling identifies an IL-6-centered and chemokine-centered inflammatory signature in ICI-My beyond background ICI exposure. Conventional cardiac biomarkers remain more informative than single cytokines for severity assessment in this cohort. IL-6R blockade appears biologically plausible and clinically feasible in selected steroid-refractory cases and warrants prospective evaluation.