Overcoming immune resistance in hepatocellular carcinoma: insights into mechanisms, predictive factors, and interventional strategies

Recently, immune checkpoint inhibitors, both as monotherapy and in combination regimens, have become a mainstay of systemic therapies for patients with advanced or unresectable hepatocellular carcinoma (HCC). However, evidence from clinical trials and real-world studies consistently demonstrates that only a subset of patients achieves long-term clinical benefit. A significant proportion of patients exhibit primary resistance or develop acquired resistance during treatment, resulting in low objective response (OR) rates, brief illness control duration, and increased complexity of successive therapeutic lines. The primary constraint in modern practice stems from the lack of reliable, generalizable, and therapeutically applicable techniques for predicting resistance to immunotherapy. This deficiency severely limits effective pretreatment risk stratification, early detection of resistance, and the formulation of rational strategies to overcome immune resistance. Therefore, this review systematically summarizes the primary causes of resistance to HCC immunotherapy, evaluates recent developments in resistance prediction, and focuses particular attention on emerging intervention strategies and potential clinical translation. Thus, it aims to offer practical guidance for enhancing treatment decision-making and to inform the development of future prospective validation studies.