Immune checkpoint inhibitor-related cardiotoxicity: a cellular pharmacology perspective on susceptibility and resistance

Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape of cancer, yet their clinical benefit is accompanied by a distinct spectrum of immune-related toxicities. Among these, cardiotoxicity remains uncommon but clinically consequential because it can evolve quickly, presents with marked heterogeneity, and may result in fulminant myocarditis, malignant arrhythmia, or hemodynamic collapse. Key mechanistic drivers include T-cell clonality directed against cardiac autoantigens (e.g., α-myosin heavy chain), cytokine amplification via JAK/STAT signaling, and innate immune recruitment. Recent work has shifted the field away from viewing ICI-related cardiotoxicity as a nonspecific inflammatory complication. Instead, available data support a model in which immune checkpoint blockade perturbs a broader tumor–host ecosystem and exposes organ-specific vulnerabilities within the heart. T-cell clonality, loss of peripheral tolerance, cytokine amplification, endothelial activation, stromal remodeling, and metabolic rewiring all appear to contribute, although their relative importance likely varies across patients. This review examines ICI-associated cardiotoxicity through the lens of cellular pharmacology. We focus on how checkpoint signaling sustains cardiac immune homeostasis, how susceptibility emerges from interactions between tumor-derived cues and host immune context, and why resistance to toxicity-directed therapy remains clinically relevant. We also discuss evolving biomarker strategies—including high-sensitivity troponins, cardiac MRI, and emerging immune-state markers—and mechanism-based interventions that may help reduce cardiac injury without fully negating antitumor efficacy. By framing cardiotoxicity as a context-dependent extension of systemic immune modulation rather than an isolated adverse event, we highlight unresolved questions that are central to the development of predictive biomarkers and more selective therapeutic strategies. Finally, we briefly note that structured nursing surveillance and multidisciplinary team coordination remain essential for translating mechanistic advances into improved bedside outcomes.