Cancer-related Immune Therapies: Bidirectional Implications from Cardiotoxicity to Emerging Cardiovascular Therapeutics: (JACC: CardioOncology State-of-the-Art Review August 2025)-Article: Cancer-related Immune Therapies: Bidirectional Implications from Cardiotoxicity to Emerging Cardiovascular Therapeutics: JACC CardioOncology State-of-the-Art Review

Article: Cancer-related Immune Therapies: Bidirectional Implications from Cardiotoxicity to Emerging Cardiovascular Therapeutics: JACC CardioOncology State-of-the-Art Review

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This state-of-the-art review in JACC CardioOncology addresses the bidirectional relationship between immune-based cancer therapies and cardiovascular disease, highlighting both cardiotoxic risks and emerging cardiovascular treatments. Immune therapies such as immune checkpoint inhibitors (ICIs), bispecific T cell engagers (BiTEs), chimeric antigen receptor (CAR) T cells, and tumor-infiltrating lymphocytes (TILs) have revolutionized oncology by activating immune responses against tumors. However, these therapies can provoke serious cardiovascular immune-related adverse events (irAEs), including myocarditis, cardiomyopathy, heart failure, accelerated atherosclerosis, and arrhythmias.<br /><br />Myocarditis induced by ICIs, characterized by infiltration of cytotoxic CD8+ T cells and macrophages in heart tissue, carries substantial mortality. Mechanistic studies reveal pathways involving autoreactive T cells, antigen-presenting dendritic cells, fibroblast-driven retention signals, and inflammatory pyroptosis mediated by gasdermin E and cGAS-STING activation. Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for ICI myocarditis. Management strategies like abatacept (a CTLA-4 agonist) combined with immunosuppressants show promising survival benefits in severe cases.<br /><br />T cell–based therapies, including CAR T cells and BiTEs, can cause cardiotoxicity primarily through cytokine release syndrome (CRS), on-target off-tumor effects, and off-target effects, resulting in left ventricular dysfunction, arrhythmias, and heart failure. Tocilizumab (an IL-6 receptor blocker) helps manage CRS. Cross-reactivity of engineered T cells with cardiac proteins, such as titin, underscores the importance of target specificity to avoid cardiac injury.<br /><br />Conversely, insights from immuno-oncology have uncovered immune checkpoint pathways as therapeutic targets in cardiovascular disease. Agents like abatacept reduce cardiac inflammation and atherosclerosis by modulating T cell activation. Targeting CD40L and CD47 pathways may stabilize atherosclerotic plaques by altering immune cell interactions and promoting efferocytosis, though safety challenges remain. CAR T cells targeting fibroblast activation protein (FAP) show potential for treating cardiac fibrosis and remodeling post-myocardial injury.<br /><br />The review emphasizes the critical need to bridge cardio-oncology and cardio-immunology to leverage immune-based therapies while minimizing cardiotoxicity. Advances in single-cell omics and preclinical models will aid in identifying pathogenic immune responses and refining immunomodulatory strategies for both cancer and cardiovascular diseases. This integrative approach holds promise for improved diagnostics, risk stratification, and development of targeted therapies to address immune-driven cardiovascular pathology.

Keywords

immune checkpoint inhibitors

cardiotoxicity

myocarditis

CAR T cells

cytokine release syndrome

abatacept

cardiovascular immune-related adverse events

clonal hematopoiesis of indeterminate potential

immune-based cancer therapies

cardio-oncology