Contemporary Use of 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 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, with a favourable safety profile. Initial treatment strategies of single-agent immune checkpoint inhibitors (ICIs) yielded only limited clinical activity. A better understanding of the hepatic tumour microenvironment and immunotolerance has driven the development of biologically relevant immunotherapy combinations. These combinations, which include anti-angiogenic agents or dual ICIs targeting both programmed cell death protein-1 (PD-1)/ programmed cell death ligands 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), are the focus of ongoing research. Recently published clinical trials involving ICI-based combination therapies achieved improved treatment outcomes and continue to reshape the treatment paradigm for advanced HCC. While the enhancement of anti-tumour immunity through different immunotherapy combinations has shown variable triumph, toxicity and costs are inevitably increased. Furthermore, the search for predictive biomarkers remains an unmet challenge in advanced HCC. In this review, we will summarize the notable advances in immunotherapy for the treatment of advanced HCC, discuss the underlying immune microenvironment and rationale for combinations, as well as explore opportunities for novel therapeutic targets beyond conventional immune checkpoints to overcome immunotherapy resistance.