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All issues Volume 6 (2025) Vis Cancer Med, 6 (2025) 1 Full HTML
Open Access
Issue
Vis Cancer Med
Volume 6, 2025
Article Number 1
Number of page(s) 6
DOI https://doi.org/10.1051/vcm/2025003
Published online 22 January 2025

© The Authors, published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

Anti-cancer immunotherapy has revolutionized oncology by leveraging the immune system to target cancer cells, offering hope for controlling advanced diseases. Immune checkpoint inhibitors (ICIs) and other immunotherapeutic agents are increasingly common, but can cause immune-related adverse effects, including toxicities in the gastrointestinal, endocrine, hepatic, and dermatologic systems [1]. Among the most concerning, is immunotherapy-related cardiotoxicity, a rare but potentially life-threatening complication, encompassing myocarditis, pericardial disease, arrhythmias, cardiomyopathy, congestive heart failure, and others [1–3]. Current treatments for immune-related adverse events (irAEs) are outlined in the Common Terminology Criteria for Adverse Events and American Society of Clinical Oncology guidelines. Steroids remain the primary treatment for cardiotoxicity or irAEs of any other organ system [1–4]. Fortunately, immunotherapy-related cardiotoxicity can be preventable and treatable with early detection and prevention. This article reviews types of immune therapies, signs of cardiovascular toxicities, and interventions to mitigate these risks, ensuring patients can benefit from these advances without compromising cardiovascular health.

Categories of immunotherapy in oncology

Table 1 summarizes types of immune therapies, their mechanisms, and approved indications. Cardiotoxicity from ICIs is rare (approximately 1%), but severe events such as refractory arrhythmia or cardiogenic shock can result in devastating clinical consequences with high mortality rates [2, 5]. The true incidence has not been fully characterized and is likely underreported, varying by rarity, immunotherapy type, cancer type, and patient factors. A contemporary comparative meta-analysis study showed treatment with ICIs was associated with a higher risk of myocarditis, pericardial disease, and MI compared with chemotherapy or placebo, though this was not reflected in observational studies [6]. Combination ICI therapy carries a higher risk and severity of cardiotoxicity than monotherapy [5, 7]. Cardiotoxicity in adoptive T-cell therapies is commonly related to cytokine release syndrome (CRS) when activation of the immune system results in a surge of cytokines and chemokines and subsequent T-cell therapy mediated tumor-cell lysis [8, 9]. Cohort studies on CAR T-cell therapy revealed 10% – 20% of patients experienced major adverse cardiovascular events, such as arrhythmias, cardiomyopathy, myocardial infarction, and heart failure [8].

Table 1

Summary of categories of immunotherapy, including subtypes, agents, mechanism of action, and approved indications for advanced solid tumors.

T-VEC, the oncolytic virus therapy for melanoma, has a low toxicity profile consisting of flu-like symptoms, such as fever, chills, and myalgia, or injection site reactions of redness or swelling. In one study assessing T-VEC in a real-life clinical setting, there was only one cardiac adverse event reported [10]. Studies on the cardiotoxic effects of anticancer vaccines are limited, but the side effects have been reported as flu-like symptoms similar to T-VEC, including fever, chills, headache, and myalgia [11].

Recent advancements in immune therapies include the development of cancer vaccines. One example is the personalized cancer vaccine developed by Moderna and Merck using V940 (mRNA-4157), a personalized neoantigen therapy using mRNA that can encode patient-specific neoantigens, to prevent melanoma recurrence. The open-label phase 2 trial revealed combining mRNA-4157 with Pembrolizumab reduced risk of recurrence or death compared to Pembrolizumab alone. The phase 3 trial of Adjuvant V940 (mRNA-4157) Plus Pembrolizumab Versus Adjuvant Placebo Plus Pembrolizumab in High-Risk Stage II–IV Melanoma Patients is expected to be complete in 2029 [12, 13]. Additionally, the SCIB1 and iSCIB1+ DNA vaccines, in phase 2 of clinical trials, have shown promise in treating melanoma. A preliminary study with SCIB1 has demonstrated a markedly enhanced T cell response, contributing to the eradication of tumors in melanoma patients [14].

Further examples of cancer vaccines include dendritic and whole cell, which employ immunotherapy cancer vaccines sipuleucel-T and Bacillus Calmette-Guérin. Usage of sipuleucel-T has resulted in significant overall survival outcomes for men with metastatic castration-resistant prostate cancer. As an active cellular immunotherapy, the vaccine generates immune responses against PAP. The bacillus Calmette-Guérin immunotherapy is effective in preventing and treating superficial bladder cancer and mechanism behind the vaccine is the potentially activation of TH1 cytokine responses [14, 15].

Symptoms, signs, and laboratory findings

Cardiotoxicity associated with immunotherapy exhibits a spectrum of clinical presentations. Symptoms are contingent upon the specific type of cardiovascular toxicity and may range from asymptomatic presentations to non-specific symptoms like fatigue and palpitations, to more severe clinical manifestations like chest pain and dyspnea and even sudden cardiac death. The median onset of symptoms varies based on the employed immunotherapeutic agents, typically occurring between three months and one year post-treatment, influenced by cancer type and cardiotoxicity nature [2, 16]. Thus, rigorous cardiovascular monitoring is crucial for early detection and management. Table 2 outlines the types of cardiotoxicity, symptoms, diagnostic tests, and potential treatments.

Table 2

Overview of common immune therapy related cardiovascular toxicities [2, 4, 17–27].

Immunotherapy-associated cardiotoxicities vary by agent, timing, and clinical presentation. Myocarditis induced by ICIs often occurs within the first three months of beginning ICI treatments. Other cardiac complications, such as myocarditis, pericarditis, and cardiomyopathy, have been discovered within 2–17 weeks following ICI treatment initiation [28]. By contrast, cardiotoxicities associated with adoptive T-cell therapies, such as CAR T-cell therapy, occur much sooner at a median of 5–21 days [29]. These differences are due to mechanistic reasons: ICI-related myocarditis may be driven by T-cell infiltration of the myocardium but CAR T-cell cardiotoxicities related to systemic inflammatory surges.

Management strategies for immunotherapy-related cardiotoxicities are generally tailored due to severity. Mild cases may respond well to temporarily ceasing immunotherapy and initiation of high-dose corticosteroids [30]. Moderate or severe cases may require more aggressive treatments or combination immunosuppression. Overall, graded approaches are essential as therapies may be elevated or depressed based on clinical response, biomarkers, and imaging findings.

Future clinical efforts are informed by advances in preclinical research. Currently, to reduce or control immunotoxicities, oncology and cardiology societies are developing new or improving upon current consensus guidelines to optimize screening, identify predictive biomarkers, and study novel therapies for mitigating risks [30]. These efforts may result in standardized clinical protocols and novel therapies that will improve patient outcomes without compromising oncologic benefits of immunotherapy.

Prevention approaches

As immunotherapy becomes more prevalent in cancer treatment, immunotherapy-related cardiotoxicity is a growing concern. Despite widespread use of these therapies, evidence-based cardiovascular screenings or preventative strategies are lacking. Understanding and mitigating this risk is crucial for optimizing patient outcomes while maximizing the therapeutic benefits of immunotherapies.

Preventing cardiotoxicity begins with risk stratification at cancer diagnosis, involving a thorough cardiovascular assessment, including obtaining cardiac history, physical examinations, and other baseline testing. Clinicians should consider factors such as pre-existing cardiovascular diseases, advanced age, and other risks before starting treatments, following guidelines outlined by the Heart Failure Association and International Cardio-Oncology Society [31]. For instance, a study by Drobni et al. shows ICI use was associated with a three-fold increase in the progression of atherosclerotic plaque [32]. Patients receiving corticosteroids during checkpoint therapy showed slower plaque progression (3.5% per year) compared to those not on corticosteroids (6.9% per year).

Many studies also call for baseline cardiac testing with ECG, cardiac stress test, echocardiogram, and troponin measurements to evaluate cardiac function, ischemic burden, and for any cardiac abnormalities prior to starting treatment [2, 6, 16, 31]. Patients at higher risk for cardiovascular toxicities are recommended to be referred to cardiologists or specialized cardio-oncologists for further evaluation and to optimize supportive strategies, such as controlling hypertension or dyslipidemia.

Ongoing monitoring of cardiac function during treatment is critical for early detection of cardiotoxicity. In high-risk patients, regular measurements of cardiac biomarkers (e.g., troponin, BNP), electrocardiograms (ECGs), and echocardiograms may help detect cardiovascular toxicities. A retrospective single center study on ICI-associated myocarditis found a strong association between an increase of cardiac biomarkers and disease severity, such as elevations in creatinine kinase, myoglobin, and troponin, occurring before symptom onset, such as diagnosis of arrhythmia or myocarditis. These cardiac biomarkers decreased after the glucocorticoid treatment with methylprednisolone, supporting the benefit of routine monitoring for early detection of immunotherapy-related cardiovascular toxicities [33].

Early referral to a cardiologist for co-management in high-risk populations, such as those with underlying heart conditions or EKGs, is crucial for preventing and managing cardiotoxicities. A multidisciplinary team of interventional cardiologists, cardiac surgeons, cardiologists, and other specialists evaluate patients’ comorbidities, clinical stability, etc. to develop a patient-specific treatment plan. The “Heart Team” (HT) approach assesses cardiovascular conditions including peripheral vascular disease, pulmonary embolism, valvular heart disease, and cardiogenic shock to gather clinical data, classifies risk factors, and potentially perform noninvasive testing before the HT meets to create a formal management recommendation [34].

Conclusion

Immunotherapy-associated cardiovascular toxicities, though rare, carry high mortality risks. Their true incidence is understudied, underreported, and expected to increase with increased immunotherapy use. Therefore, developing strategies for risk stratification, prevention, and monitoring is essential. As understanding of these cardiotoxicities evolve, new prevention and management approaches are likely.

Early recognition of symptoms, comprehensive cardiac assessments with baseline diagnostics, and a multidisciplinary approach can help minimize the risk of adverse cardiovascular events.

Funding

This research received no external funding.

Conflicts of interest

The authors have nothing to disclose.

Data availability statement

This article has no associated data generated

Author contribution statement

Conceptualization, Y.X., H.T.W.; Methodology, Y.X.; Validation, Y.X., H.T.W.; Visualization, Y.X., H.T.W.; Formal Analysis, Y.X., H.T.W., S.W.; Investigation, Y.X.; Resources, Y.X.; Data curation, Y.X., H.T.W., V.H., S.W.; Writing – Original Draft Preparation, Y.X., H.T.W., S.W.; Writing – Review & Editing, All authors; Supervision, Y.X.; Project Administration, Y.X.

Ethics approval

Ethics approval was not required.

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Cite this article as: Wu HT, Hsu V, Win S & Xing Y. Anti-cancer immunotherapy-related cardiotoxicity: preventable and treatable. Visualized Cancer Medicine. 2025. 6, 1. https://doi.org/10.1051/vcm/2025003.

All Tables

Table 1

Summary of categories of immunotherapy, including subtypes, agents, mechanism of action, and approved indications for advanced solid tumors.

In the text
Table 2

Overview of common immune therapy related cardiovascular toxicities [2, 4, 17–27].

In the text

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