Eric H. Yang

Permissive cardiotoxicity is an evolving clinical practice pattern that balances the management of cancer treatment‐associated cardiotoxicities with the risk of interrupting lifesaving or life‐extending cancer treatments. This paradigm shift has been catalyzed by advancements in the diagnostic and therapeutic tools available to treating clinicians, as well as a recognition of the consequences of withholding or delaying cancer therapy. Permissive cardiotoxicity has become a central tenet in the practice of cardio‐oncologists; however, recognition and confidence in managing cardiotoxicity is also crucial for the general cardiologist and oncologist due to the growing population of patients with cancer. This review aims to (1) highlight the philosophy of permissive cardiotoxicity, (2) provide a framework for risk stratification of cardiovascular toxicities, (3) describe systems of care considerations for successful implementation of permissive cardiotoxicity, and (4) review the existing literature and guideline recommendations for specific cardiovascular toxicity mitigation.

Sex differences influence cancer incidence, treatment response, and susceptibility to cardiovascular toxicity. Males exhibit higher rates and poorer outcomes in most non-sex-specific cancers, while females more frequently experience treatment-related adverse events, including cancer therapy-related cardiac dysfunction. Biological factors such as hormonal status, genetic polymorphisms, immune responses, and pharmacokinetics contribute to these disparities. In cardio-oncology, women—particularly premenopausal or with specific genotypes—may be at increased risk for cardiotoxicity after treatment with anthracyclines, immune checkpoint inhibitors or radiotherapy. Clonal hematopoiesis and certain germline genetic variants such as single nucleotide polymorphisms (e.g., RARG rs2229774, HAS3 rs2232228) are emerging as potential sex-informed biomarkers for predicting cardiotoxicity risk. Despite growing evidence, sex remains insufficiently integrated into clinical trials and guideline development in cardio-oncology. This review highlights the importance of sex-specific surveillance, prevention, and multi-omic risk stratification to advance precision cardio-oncology and support better outcomes for patients across the cancer care continuum.

Immune checkpoint inhibitor (ICI) therapy is a class of immune‐activating therapies that has revolutionized the treatment of various cancers over the past decade. With expanding clinical indications of this drug class, understanding the short‐term and long‐term implications of checkpoint inhibitor therapy has grown in importance. Numerous reports have highlighted potential inflammatory adverse effects, including cardiotoxicity. Efforts to characterize cardiovascular adverse events, however, have largely focused on myocarditis with emerging evidence demonstrating the association between ICI therapies and atherosclerotic cardiovascular disease. Given the inherently higher risk of thrombosis and bleeding in patients with cancer, the safe and effective management of ICI‐associated acute coronary syndrome remains a therapeutic challenge requiring a tailored and multidisciplinary approach. In this review, we discuss the pathophysiology of ICI‐associated atherosclerosis, the complexities of acute coronary syndrome management in patients with cancer, and the opportunities for risk prevention in patients receiving ICI therapies.

T cell immunotherapies offer a new approach to cancer therapy. Chimeric antigen receptor (CAR) T cell therapy is the most prolific of these treatments, leveraging genetically engineered T cells to augment the antitumour response. Bispecific antibodies, T cell receptor-engineered T cells and tumour-infiltrating lymphocytes have also emerged as novel T cell therapies with therapeutic benefit. As the variety of T cell therapies and indications for their use expand, a nuanced understanding of potential haemodynamic sequelae and cardiovascular toxicities is required. T cell activation can lead to massive cytokine release and excessive inflammation, termed cytokine release syndrome (CRS). Like other inflammatory syndromes, CRS can lead to cardiovascular complications, including arrhythmias, myocardial infarction and heart failure, with an incidence of cardiovascular events as high as 20% among patients who develop high-grade CRS. In this Review, we summarize the mechanisms, epidemiology and management of T cell therapy-associated CRS and subsequent cardiotoxicity. We also explore how an improved understanding of CAR T cell therapy, and other emerging T cell-based treatments, will inform the prevention and management of adverse cardiovascular events.