Systemic Therapy for Advanced Hepatocellular Carcinoma in 2026: Current Standard-of-Care and Emerging Therapeutic Strategies.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, accounting for up to 80% of all cases. Most patients present at an advanced stage and are unsuitable for curative treatments. In the past 5 years, immunotherapy combination has superseded tyrosine kinase inhibitors (TKI) as the standard first-line therapy for advanced HCC. These therapies include the combination of anti-PD-(L)1 with an anti-CTLA-4 or partner with anti-VEGF; these agents offer unprecedented high rates of response and survival. Unfortunately, only about 20%-30% of patients respond to first-line immunotherapy combination, and about 50% of them would develop disease progression at 6 months. In patients with progression on immunotherapy, recent prospective studies support the efficacy and safety of multiple TKIs. To further improve the efficacy of systemic therapies, novel therapeutic strategies are actively being investigated, such as with the addition of a third immune checkpoint inhibitor. Furthermore, there is increasing interest to incorporate locoregional therapies in patients with advanced disease. Three Phase 3 randomized studies (EMERALD-1, LEAP-012, and TALENTACE) have recently demonstrated survival benefits with the combination of trans-arterial chemoembolization (TACE) and immunotherapy, over TACE alone. The higher response rates brought by combining locoregional therapies and systemic therapies have enabled the possibility of downstaging and conversion. In addition, cellular therapy has shown promise in early phase studies, demonstrating potential to expand the use of immunotherapy in HCC beyond immune checkpoint inhibitors. In this review, we provide an overview of the current treatment landscape and emerging therapeutic strategies for advanced HCC.