Synergistic PD-1/PD-L1 Blockade Strategies in Hepatocellular Carcinoma Management

Primary liver cancer ranks as the sixth most commonly diagnosed malignancy and the third leading cause of cancer-related mortality worldwide. Treatment at early stages primarily involves surgical resection; however, more than 70% of patients are diagnosed at intermediate or advanced stages according to the Barcelona Clinic Liver Cancer (BCLC) staging system. At these stages, curative-intent surgery is often precluded due to vascular invasion or extrahepatic metastasis. Immunotherapy, especially inhibitors targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, has emerged as a promising therapeutic strategy. Nevertheless, its application is constrained by challenges such as immune-related adverse events (irAEs) and the development of acquired resistance to immune checkpoint inhibitors (ICIs). To overcome these limitations, combination therapeutic approacheswhich target both the tumor microenvironment and the host immune systemhave been extensively investigated. These regimens not only improve antitumor efficacy but also help mitigate resistance mechanisms. This review comprehensively summarizes recent advances in combination strategies for unresectable liver cancer, including immunetargeted, immuneradiotherapy, and immunechemotherapy combinations, with the aim of providing valuable insights and clinical guidance for improving outcomes in this patient population.