Cardiac Organoids for Mechanistic and Predictive Assessment of Chronic Cardiotoxicity

Chronic cardiotoxicity remains a major unmet challenge in drug development, particularly for oncology and immunotherapy, where cardiovascular complications may emerge months to years after treatment and persist long after drug exposure. Current approaches remain predominantly optimized for acute or short-term toxicity and have limited capacity to capture the cumulative and remodeling-driven processes underlying delayed cardiac dysfunction, including mitochondrial impairment, extracellular matrix remodeling, fibrosis, and progressive loss of contractile reserve. Human-induced pluripotent stem cell-derived cardiomyocytes have improved early safety screening but remain limited by immaturity and lack of multicellular complexity. Cardiac organoids offer a promising alternative by recapitulating tissue architecture, cell–cell interactions, extracellular matrix remodeling, and long-term functional dynamics. In this review, we examine the biological mechanisms and clinical manifestations of chronic cardiotoxicity, critically evaluate existing experimental models, and define the unique opportunities and remaining limitations of cardiac organoids for delayed toxicity prediction. We propose a staged framework for integrating organoid-based assays into drug discovery pipelines and discuss maturation strategies, organoid-on-chip integration, and regulatory considerations necessary for more predictive and mechanistically informed drug safety evaluation.