Checkpoint inhibitor therapy revolutionized the treatment of patients with melanoma. However, in patients where melanoma exhibits resistance to checkpoint inhibitor therapy, the treatment options are limited. Oncolytic viruses are a unique form of immunotherapy that uses live viruses to infect and lyse tumor cells to release the elusive neoantigen picked up by the antigen-presenting cells, thus increasing the chances of an immune response against cancer. Coupled with checkpoint inhibitors, intratumoral injections of the oncolytic virus can help an enhanced immune response, especially in a tumor that displays resistance to checkpoint inhibitors. However, oncolytic viruses are not bereft of challenges and face several obstacles in the tumor microenvironment. From the historical use of wild viruses to the sophisticated use of genetically modified viruses in the current era, oncolytic virus therapy has evolved tremendously in the last two decades. Increasing the ability of the virus to select the malignant cells over the non-malignant ones, circumventing the antiviral immune response from the body, and enhancing the oncolytic properties of the viral platform by attaching various ligands are some of the several improvements made in the last three decades. In this manuscript, we trace the journey of the development of oncolytic virus therapy, especially in the context of melanoma. We review the clinical trials of talimogene laherparepvec in patients with melanoma. We also review the data available from the clinical trials of vusolimogene oderparepvec in patients with melanoma. Finally, we review the use of various oncolytic viruses and their challenges in clinical development. This manuscript aims to create a comprehensive literature review for clinicians to understand and implement oncolytic virus therapy in patients diagnosed with melanoma.

Neoadjuvant use of immune checkpoint inhibitors (ICIs) is the new standard of care in patients with clinical stage III melanoma. However, it is associated with immune‐related adverse events (irAEs). Nivolumab–relatlimab in the neoadjuvant setting is an NCCN‐recommended treatment for patients with clinical stage III melanoma. Anti‐LAG3 molecule comes with an increased risk of cardiac irAE, especially myocarditis. Takotsubo cardiomyopathy (TTC), a reversible decline in heart function driven by catecholamine overload, is reported as a cardiac irAE in the literature. However, the mechanism of TTC being an irAE is elusive. It is known that myocarditis and TTC share a lot of common features, although the presence of cardiac inflammation essentially rules out TTC. Here, we report the case of an elderly patient with a history of heart failure with midrange ejection fraction, diagnosed with clinical stage III melanoma, who developed shortness of breath with the first dose of neoadjuvant nivolumab–relatlimab. Cardiac magnetic resonance (CMR) imaging demonstrated a severe apical hypokinesis and no myocardial edema, suggestive of TTC. However, since myocarditis could not be ruled out, the patient was started on high‐dose methylprednisolone followed by a 9‐week taper of prednisone. The CMR changes reverted to baseline 44 days later, with the patient experiencing complete recovery. He underwent wide local excision of the primary melanoma and complete lymph node dissection, which showed a major pathologic response. Postoperatively, he remains on surveillance with no evidence of recurrence. This report emphasizes early recognition of cardiac irAEs and initiation of corticosteroids, which could help prevent morbid long‐term complications.