Prediction of Response to Immunotherapy in Hepatocellular Carcinoma: Where Do We Stand?

Worldwide, liver cancer is the seventh most common cancer and the third leading cause of cancer-related mortality, reflecting its dismal prognosis, with only approximately 20% of patients alive 5 years after diagnosis. At least 50% of patients ultimately require systemic treatment. In 2020, the systemic treatment landscape changed dramatically with the introduction of immune checkpoint inhibitor (ICI)-based therapies, which have demonstrated improved overall survival and longer preservation of quality of life compared with tyrosine kinase inhibitor (TKI)-based approaches. However, fewer than one third of patients achieve objective response, 10-25% experience severe immune-related adverse events, and ICI-based treatments represent a substantial economic burden for health systems. Importantly, robust and clinically validated predictive biomarkers of response to ICI remain an unmet need. This review summarizes current efforts to identify predictive biomarkers of ICI response in hepatocellular carcinoma (HCC), integrating clinical, pathological, molecular, microbiome, and imaging approaches, and discusses how these developments may shape the future of treatment selection.