From Viral Oncogenesis to Dual Checkpoint Blockade: A Comprehensive Review of Hepatocellular Carcinoma Biology, Treatment and Guideline Evolution

Hepatocellular carcinoma (HCC) is the leading primary liver cancer and remains one of the deadliest malignancies globally. Its incidence continues to rise, driven by chronic viral hepatitis in the Eastern countries and metabolic liver disease in the Western countries. Landmark phase III trials have transformed the landscape of systemic therapy: atezolizumabbevacizumab, durvalumabtremelimumab, and nivolumabipilimumab each deliver superior survival over sorafenib and are now first-line standards. Parallel studies are testing these agents in adjuvant, neoadjuvant, and locoregional combinations, signalling a shift toward earlier immunologic intervention. Yet the field still lacks validated biomarkers and globally harmonised treatment algorithms. This review compiles current evidence on worldwide epidemiology of HCC, key risk factors such as HBV, aflatoxin exposure and NAFLD, and the molecular pathways that drive hepatocarcinogenesis. It critically compares the design, efficacy and safety of major immunotherapy trials and summarises ongoing studies that combine systemic agents with surgery, ablation or transarterial chemo-embolisation. By mapping existing data to current unmet needs, this analysis highlights key opportunities for advancing biomarker-guided precision therapy and expanding access to novel treatments in resource-limited settings.