Chimeric antigen receptor-T cell therapy-induced cardiotoxicity: Pathophysiological mechanisms and pharmacological intervention strategies

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a revolutionary treatment for hematologic malignancies and solid tumors. Multiple approved products and ongoing clinical trials have demonstrated its remarkable antitumor efficacy. However, its clinical application is severely limited by prominent cardiotoxicity, which is closely associated with high morbidity and mortality, posing an urgent clinical challenge. This review systematically elucidates the pathophysiological mechanisms underlying CAR-T cell therapy-induced cardiotoxicity, which can be primarily categorized into acute and long-term adverse effects. Acute cardiotoxicity is driven by cytokine release syndrome (CRS) through macrophage and monocyte activation, endothelial dysfunction, and subsequent myocardial injury, leading to hypotension, reduced left ventricular ejection fraction, and cardiac arrhythmias. Long-term cardiotoxicity is mainly caused by B-cell aplasia-induced immune deficiency and secondary hemophagocytic lymphohistiocytosis, which trigger infectious complications, myocardial ischemia, and apoptosis. We have further summarized clinical pharmacological interventions for such cardiotoxicity, including interleukin (IL)-6 receptor antagonists (tocilizumab), interferon-γ inhibitors (emapalumab), and Janus kinase inhibitors (ruxolitinib). However, none of these drugs can completely alleviate CRS or CAR-T cell therapy-induced cardiotoxicity in all patients. Preclinical agents targeting inflammatory cytokines (IL-1β, tumor necrosis factor-α) and signaling pathways have shown efficacy in ameliorating cardiotoxicity in various animal models. These findings provide novel directions and drug candidates for the treatment of CAR-T cell therapy-induced myocardial toxicity. This review provides a comprehensive theoretical basis for optimizing cardiovascular safety management and developing novel targeted interventions for CAR-T cell therapy.