Background: Lung cancer remains the primary cause of cancer-related mortality globally, treated using immune checkpoint inhibitors (ICIs), which are introducing new therapeutic potential and complexities, including severe immune-related adverse events (irAEs) and rare fistula formation. The interaction between coronavirus disease 2019 (COVID-19) and ICIs further complicates treatment outcomes, occasionally leading to spontaneous tumor regression, suggesting potential immune response modulation by COVID-19. This report elucidates a unique case of non-small cell lung cancer (NSCLC) managed with these challenges, highlighting the delicate balance required for modern oncological care., Case Description: A 44-year-old male patient with stage IIIC NSCLC, no driver mutations such as those in epidermal growth-factor receptor ( EGFR ) or anaplastic lymphoma kinase ( ALK ) genes, and a tumor proportion score of <1% experienced multiple complications after ICI plus chemotherapy. The treatment regimen comprised durvalumab, tremelimumab, carboplatin, and nab-paclitaxel. The patient experienced multiple complications including: (I) esophageal mediastinal fistula; (II) severe irAEs such as grade 3 colitis; (III) COVID-19 and Candida albicans infections; (IV) cytokine release syndrome; and (V) myocarditis. Treatment interventions included high-dose steroids, antifungal therapy, mechanical support in the intensive care unit, and hemodialysis. The patient showed remarkable tumor regression and recovery from acute adverse events with eventual tumor resolution and closure of the esophageal mediastinal fistula. Tumor cells were positive for angiotensin-converting enzyme 2, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have infected tumor cells and caused an antitumor effect as an oncolytic virus., Conclusions: Clinicians should be aware that COVID-19 might be associated with the development of severe irAEs and unexpectedly enhanced antitumor effects. The findings also suggest new fields of study regarding the interaction between viral infection and tumor immune response, which may inform future therapeutic approaches., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-444/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)