Immune checkpoint inhibitors (ICIs) are revolutionary oncologic therapies used frontline in several malignant neoplasms, including non–small cell lung cancer, melanoma, renal cell carcinoma, bladder cancer, and colorectal cancer. However, because these agents modify immunoregulatory pathways, they carry a risk of adverse events across multiple organ systems (Table 1).¹ Myocarditis cases continue to rise given the expanded use of ICIs, although the fatality rates appear to be declining, likely due to earlier detection and prompt initiation of rescue agents.²

Table 1: Summary of ICI and 5-FU Toxicities

5-FU = 5-fluorouracil; ACS = acute coronary syndrome; CM = cardiomyopathy; CS = cardiogenic shock; HF = heart failure; ICI = immune checkpoint inhibitor.

ICIs are now commonly combined with other anticancer agents with known cardiotoxic effects such as anthracyclines (left ventricular dysfunction/heart failure) and tyrosine kinase inhibitors (hypertension). There is limited understanding of the combined and additive effects of these therapies on CV events. An example of combination anticancer therapy with an ICI and antimetabolite chemotherapy (FOLFOX [folinic acid, fluorouracil, oxaliplatin]) with stage III deficient DNA mismatch repair (dMMR) colon cancer was recently published (the ATOMIC [Adjuvant Trial of Deficient Mismatch Repair in Colon Cancer] phase 3 trial).³ The standard treatment for stage III dMMR colon cancer has traditionally been surgical resection followed by adjuvant FOLFOX. dMMR colon cancer represents approximately 15% of patients in the stage II/III setting.

In the ATOMIC, 712 patients were randomly assigned to receive either FOLFOX and atezolizumab (a programmed death ligand-1 [PD-L1] ICI) for 6 months followed by atezolizumab alone for 6 months or FOLFOX alone for 6 months. At 36 months, the disease-free survival rate was 86.4% in the atezolizumab arm and 76.6% in the FOLFOX arm. There was a consistent effect across multiple subgroups. Of note, the most common adverse events in both groups included fatigue, nausea, peripheral sensory neuropathy, and decreased neutrophil/platelet counts. Although cardiotoxicity was not listed as an immune-related adverse event (iRAE) overall, the atezolizumab group contained more grade ≥3 adverse events than did the FOLFOX-only group. PD-L1 agents such as atezolizumab have traditionally been associated with reduced iRAEs compared with their programmed death receptor-1 (PD-1) counterparts.³

The ATOMIC findings will likely lead to more patients receiving both ICI and FOLFOX concurrently and real-world experience will determine optimal management. Until evidence is available, clinicians must consider several potential causes in the workup of patients with symptoms. Chest pain due to coronary vasospasm with potential ST-segment elevation myocardial infarction may occur in up to 10% of patients treated with 5-fluorouracil (5-FU) (Table 1). In addition, patients can develop acute cardiomyopathy.⁴ ICI myocarditis is uncommon (~1%) but ranges in severity and mortality is high. Therefore, prompt recognition is critical. Presentation may include chest pain, dyspnea, fatigue, and myositis.⁵ Electrocardiogram (ECG) abnormalities (QTc prolongation, QRS ≥120 msec, atrioventricular block, bundle branch block, ST-segment abnormalities, and T-wave changes) at admission were more common in patients with ICI myocarditis who experienced major adverse cardiac events.⁶ In another study, sinus tachycardia and QTc prolongation were associated with risk of severe ICI myocarditis.⁷ Both ICI myocarditis and 5-FU coronary vasospasm typically present within the first 1-2 months of exposure. Animal and cellular models have also demonstrated the potential for ICI therapy to accelerate atherosclerosis, and results from a retrospective study have shown an increase in total aortic plaque with a higher risk of atherosclerotic cardiovascular (CV) events after ICI treatment.¹ This may lead to elevated composite risk of coronary events when combined with 5-FU and should be prepared for accordingly.

Dihydropyrimidine dehydrogenase (DPYD) genotyping is now an increasingly recommended component of pretreatment fluoropyrimidine safety assessment. In 2026, the Food and Drug Administration (FDA) labeling for 5-FU and capecitabine was updated to include a boxed warning for serious adverse reactions or death in patients with complete dihydropyrimidine dehydrogenase deficiency and advises testing for DPYD variants before treatment unless immediate therapy is necessary. National Comprehensive Cancer Network (NCCN) guidelines now state that DPYD testing should be considered prior to fluoropyrimidine therapy, with recognition that currently available assays vary in the number and type of variants detected. The role of DPYD genotype in the risk of cardiotoxicity is less established. Current recommendations for baseline testing in patients receiving ICIs include cardiac troponin and ECG. Baseline echocardiography may be performed in patients at high risk. Whether enhanced baseline and follow-up CV surveillance for patients taking combined ICI and 5-FU regimens is beneficial remains to be seen.

Initial management of patients receiving 5-FU and ICI therapy with angina or equivalent symptoms typically includes evaluation for coronary disease with ECG, troponin, and, if indicated, a computed tomography coronary or catheter angiography. Revascularization may be indicated in the setting of a clear acute coronary syndrome. In the setting of stable angina and potential coronary vasospasm, the stopping of 5-FU and subsequent rechallenge with pretreatment calcium channel blockers and nitrates have demonstrated efficacy.⁸ Additionally, evaluation for myocarditis should be pursued if coronary vasospasm related to 5-FU is not suspected. Although rare, cardiogenic shock and cardiomyopathy have been reported in patients taking 5-FU. In a patient taking combination 5-FU and ICI therapy with a cardiomyopathy who is decompensated, treating empirically for both while pursuing further diagnostic workup may be necessary. The antidote for severe 5-FU toxicity is uridine triacetate, which should be given within 96 hours of cardiotoxicity, although cost and availability limit use.⁹ Standard treatment for ICI myocarditis includes initiation of high-dose corticosteroids (methylprednisolone 1000 mg/day) and, in refractory cases, consideration of abatacept, Janus kinase inhibitors, plasmapheresis, intravenous immunoglobulin, and mycophenolate mofetil.¹⁰ Rechallenge with ICI is considered contraindicated but reports of safe rechallenge make this an individualized decision, incorporating assessment of myocarditis severity, available alternative therapy, immunosuppressant effectiveness, and patient preference. Alternative ICIs should be considered, and limited data suggest anti–PD-1 agents may demonstrate a lower risk of cardiotoxicity.²

As addition of ICI to cancer treatment regimens becomes increasingly standard, clinicians must be vigilant to collect more data on their combined cardiotoxic profile. Rechallenge should be individualized and involve multidisciplinary discussion based on the prognosis of the malignant neoplasm and severity of the cardiotoxicity. Further research and experience with these agents will enable patients to navigate their therapeutic course more safely in the future.

References

1. Herrmann J, Barac A, Carver J, et al. Immune checkpoint inhibitor-associated cardiovascular toxic effects: International Cardio-Oncology Society position statement. JAMA Oncol. 2026;12(1):90-99. doi:10.1001/jamaoncol.2025.4543
2. Reeves DJ, Leffers K, Rao VU. Immune checkpoint inhibitor related myocarditis reported through the FDA adverse event reporting system: pharmacovigilance trends in reporting and outcomes. Front Oncol. 2025;15:1498817. Published 2025 Feb 27. doi:10.3389/fonc.2025.1498817
3. Sinicrope FA, Ou FS, Arnold D, et al. Atezolizumab plus FOLFOX for stage III mismatch repair-deficient colon cancer. N Engl J Med. 2026;394(12):1155-1166. doi:10.1056/NEJMoa2507874
4. More LA, Lane S, Asnani A. 5-FU cardiotoxicity: vasospasm, myocarditis, and sudden death. Curr Cardiol Rep. 2021;23(3):17. Published 2021 Feb 3. doi:10.1007/s11886-021-01441-2
5. Moslehi J, Lichtman AH, Sharpe AH, Galluzzi L, Kitsis RN. Immune checkpoint inhibitor-associated myocarditis: manifestations and mechanisms. J Clin Invest. 2021;131(5):e145186. doi:10.1172/JCI145186
6. Oksen D, Gecit MH, Arslan S, et al. Detecting subclinical cardiotoxicity during immune checkpoint inhibitor therapy: a combined GLS and ECG repolarization analysis. Front Oncol. 2025;15:1615209. Published 2025 Jul 8. doi:10.3389/fonc.2025.1615209
7. Gao Y, Zhang H, Qiu Y, Bian X, Wang X, Li Y. Early identification of severe immune checkpoint inhibitor associated myocarditis: from an electrocardiographic perspective. Cancer Med. 2024;13(15):e7460. doi:10.1002/cam4.7460
8. Padegimas A, Carver JR. How to diagnose and manage patients with fluoropyrimidine-induced chest pain: a single center approach. JACC CardioOncol. 2020;2(4):650-654. Published 2020 Nov 17. doi:10.1016/j.jaccao.2020.06.012
9. Raber I, Frazer MB, Zerillo JA, Asnani A. Uridine triacetate for severe fluoropyrimidine cardiotoxicity in a patient with thymidylate synthase gene variants. JACC CardioOncol. 2020;2(2):329-332. Published 2020 Jun 16. doi:10.1016/j.jaccao.2020.04.005
10. Nielsen DL, Juhl CB, Nielsen OH, Chen IM, Herrmann J. Immune checkpoint inhibitor-induced cardiotoxicity: a systematic review and meta-analysis. JAMA Oncol. 2024;10(10):1390-1399. doi:10.1001/jamaoncol.2024.3065