Glucocorticoid resistant ICI associated myocarditis is defined by an interferon gamma driven myeloid inflammatory signature

Background Immune checkpoint inhibitor–associated myocarditis (ICI-myocarditis) is a severe immune-related adverse event with high early morbidity and mortality. Although high-dose glucocorticoids (GC) are recommended as first-line therapy, a relevant subset of patients exhibits persistent myocardial inflammation despite treatment. The immunopathological mechanisms underlying glucocorticoid resistance remain poorly defined. Methods We retrospectively analyzed 74 patients with ICI-myocarditis treated between 2019 and 2025. Patients receiving glucocorticoids were classified as glucocorticoid-sensitive (GC-S, n=25) or glucocorticoid-refractory (GC-R, n=23) according to serial high-sensitivity cardiac troponin kinetics after GC initiation. Major adverse cardiovascular events (MACE) and survival were assessed. snRNA-seq was performed on endomyocardial biopsy specimens from GC-S (n=2) and GC-R (n=4) patients. Cell-type composition, immune cell subsets, and pathway-level differential gene expression were analyzed using pseudobulk approaches. Results GC-R patients showed significantly higher baseline hs-cTnT levels and persistent or recurrent troponin elevation despite GC therapy, accompanied by a markedly increased risk of early MACE within 90 days (hazard ratio 3.5, 95% CI 1.1–11.0; p=0.032). snRNA-seq revealed a distinct inflammatory myocardial immune landscape in GC-R myocarditis, characterized by expansion of myeloid cell populations, particularly macrophages and monocyte subsets. Differential expression analyses demonstrated upregulation of interferon-γ–responsive genes and chemokine signaling pathways in GC-R patients, consistent with sustained immune activation and impaired steroid responsiveness. In contrast, GC-S myocarditis exhibited a comparatively attenuated inflammatory transcriptional profile. Escalation of immunosuppression with mycophenolate mofetil in GC-R patients was associated with subsequent attenuation of cardiac biomarker levels. Conclusions Glucocorticoid-refractory ICI-myocarditis represents a distinct immunopathological entity driven by interferon-γ–associated myeloid inflammation and is associated with early clinical deterioration. Integration of biomarker dynamics with transcriptomic profiling may enable early identification of steroid-resistant disease and inform personalized immunomodulatory treatment strategies in cardio-oncology.