Kathrynne Warrick, Chandrashekhar Pasare et al. show that PD-1 blockade leads to de novo priming of self-reactive CD8 T cells resulting in immune related adverse events.

Immune checkpoint inhibitors (ICIs) improve cancer survival but can trigger immune-related adverse events. Among these, fulminant myocarditis is an often fatal complication with limited therapies. We developed a mouse model employing cardiomyocyte-restricted antigen expression to define how ICIs drive cardiac autoimmunity. Combined cytotoxic T cell antigen-4 (αCTLA-4) and programmed death-1 (αPD-1) blockade uniquely induced robust expansion of antigen-specific CD8 T cells, myocardial inflammation, and lethal arrhythmias. PD-1 blockade alone permitted the priming and effector differentiation of naive autoreactive CD8 T cells, whereas concomitant CTLA-4 inhibition amplified cardiac pathology. Unexpectedly, myocardial injury was independent of perforin-mediated cytotoxicity but critically depended on T cell–derived TNF, which promoted myeloid recruitment, cytokine production, and arrhythmogenesis. Genetic ablation of CD8 T cell–derived tumor necrosis factor (TNF) or TNF receptor 2 (TNFR2) blockade prevented cardiotoxicity while preserving antitumor efficacy. These findings establish a TNF-TNFR2–driven inflammatory circuit downstream of autoreactive CD8 T cells as a central mechanism of ICI myocarditis and a strategy to uncouple cardiotoxicity from immunotherapy benefits.