Systemic therapy for HCC: Doublets, triplets and beyond

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with most patients requiring systemic therapy at diagnosis or during disease progression. Immune checkpoint inhibitor (ICI)-based combinations have transformed the therapeutic landscape and are now the standard first-line treatment, demonstrating improved survival and higher response rates compared with earlier tyrosine kinase inhibitor-based approaches. Attempts to further improve outcomes through triplet immunotherapy strategies have so far failed to show clear clinical benefit and are often associated with increased toxicity. Emerging therapeutic approaches - including bispecific antibodies, cellular therapies, cancer vaccines, oncolytic viruses, and novel molecularly targeted agents - are currently under clinical investigation. However, the biological heterogeneity of HCC and the lack of robust predictive biomarkers remain major challenges. This review summarises current systemic therapies for advanced stages of HCC and discusses emerging strategies and biomarker approaches that may enable more precise and effective treatment selection in the future.