Immune checkpoint inhibitor (ICI)-based combination therapy has transformed the treatment of advanced hepatocellular carcinoma (HCC), yet immune-related adverse events (irAEs) remain a serious and potentially fatal complication. We report two cases of severe irAEs following ICIbased therapy for HCC. In Case 1, a man with multimetastatic HCC developed immune-mediated colitis with hemodynamic collapse and multi-organ failure after the second cycle of the STRIDE regimen yet achieved a near-complete oncologic response. In Case 2, a patient who had tolerated 17 cycles of adjuvant atezolizumab (ate) plus bevacizumab (bev) without irAE developed fatal immune-mediated fulminant hepatitis after a single dose of ate+bev reinitiated as first-line therapy for unresectable HCC following recurrence and TACE failure. These cases highlight the unpredictability of irAEs—even in previously tolerant patients—and underscore the importance of early recognition and prompt management.

Immune checkpoint inhibitors (ICIs) have robust therapeutic efficacy, offering sustained clinical benefit in various malignancies. However, the optimal duration of treatment remains under investigation. This review summarizes recent trends in long-term ICI therapy, with particular focus on hepatocellular carcinoma (HCC). The conventional 2-year treatment limitation, initially based on data from non-small cell lung cancer trials (e.g., KEYNOTE-010, Check-Mate-017), has been adopted broadly across tumor types. Follow-up data suggest that many patients maintain remission even after discontinuation of treatment, prompting reevaluation of prolonged therapy necessity. In HCC, atezolizumab plus bevacizumab has become the firstline standard treatment, but questions persist regarding continuation beyond two years and post-progression management. Emerging data indicate that salvage therapies—including tyrosine kinase inhibitors like sorafenib or lenvatinib—remain viable options after ICI failure. Furthermore, recent studies from European cohorts and Asian populations have provided insights into long-term survival, treatment sequencing. This review aims to provide a clinical and practical overview of these evolving paradigms to guide personalized, evidence-based decisions in immune-oncology.