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.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, and therapeutic cancer vaccines have emerged as a promising immunotherapeutic strategy. These vaccines target tumor-associated antigens such as glypican-3, alpha-fetoprotein, melanoma-associate antigen-1, heat shock protein 70, glutamine synthetase, and TMEM176A/B, which are abnormally expressed in HCC cells and serve as both diagnostic markers and therapeutic targets. Various vaccine platforms—including peptide-based, dendritic cells-based, viral vector-based, and genetic vaccines (DNA/mRNA)—are under investigation for their ability to elicit antigen-specific cytotoxic T cell responses and establish long-term immune memory. Despite promising preclinical and early clinical results, challenges such as the immunosuppressive tumor microenvironment, antigen heterogeneity, and immune evasion mechanisms limit their efficacy. Future strategies focus on combination therapies with immune checkpoint inhibitors, personalized neoantigen vaccines, and advanced delivery technologies. These approaches aim to enhance immunogenicity and clinical outcomes, positioning therapeutic cancer vaccines as a key component of precision oncology in HCC.