Combined Immunotherapy in Treating Patients with Advanced Hepatocellular Carcinoma.

Advanced hepatocellular carcinoma (HCC) exhibits a poor prognosis. Immunotherapy has emerged as a major player for both the upfront treatment of advanced HCC and disease progression on prior systemic therapies. In the first-line treatment of advanced HCC, immunotherapy demonstrated superior efficacy outcomes compared to tyrosine kinase inhibitors and a favourable safety profile. Initial treatment strategies of single-agent immune checkpoint inhibitors (ICIs) yielded only limited clinical activity. A deeper understanding of the hepatic tumour microenvironment and immunotolerance has driven the development of biologically relevant immunotherapy combinations. These combinations, which include antiangiogenic agents or dual ICIs targeting both PD-1/PD-L1 and CTLA-4, are the focus of current research. Recently published clinical trials involving ICI-based combination therapies achieved improved treatment outcomes, continuing to reshape the treatment paradigm for advanced HCC. While different immunotherapy combinations have shown variable efficacy in augmenting anti-tumour immunity, they inevitably increase toxicity and costs. Furthermore, the search for predictive biomarkers remains an unmet challenge in advanced HCC. In this review, we will summarise the notable advances in immunotherapy for the treatment of advanced HCC, discuss the underlying immune microenvironment and rationale for combinations, and explore opportunities for novel therapeutic targets beyond conventional immune checkpoints to overcome immunotherapy resistance.