CTLA-4/PD-1, LAG-3, and TIGIT Inhibitors: Emerging Drug Targets and Combination Strategies in Hepatocellular Carcinoma

Abstract:

Hepatocellular carcinoma (HCC) remains one of the most important causes of cancer-related death worldwide due to late diagnosis, chronic liver disease, and the highly immunosuppressive tumour microenvironment that favors immune escape and therapeutic resistance. Recently, immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte- associated antigen-4 (CTLA-4) have significantly improved the treatment of advanced HCC, especially when used in combination therapy, resulting in stronger antitumour immune responses. Several major clinical trials such as IMbrave150, HIMALAYA and Check Mate-9DW have confirmed that immune checkpoint inhibitor combinations are valuable first-line treatment options for unresectable HCC. However, primary and acquired resistance remain a major challenge to achieving durable clinical responses, and new treatment strategies are needed. Other immune checkpoint molecules, such as lymphocyte activation gene-3 (LAG-3) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), have demonstrated significant potential as novel targets for immunotherapy, due to their role in T-cell exhaustion, natural killer cell dysfunction, and adaptive immune escape. This review highlights the molecular mechanisms, preclinical and clinical evidence, and therapeutic potential of CTLA-4/PD-1, LAG-3, and TIGIT inhibitors, particularly in dual and triplet combination approaches. It also discusses mechanisms of resistance, patient stratification using biomarkers, and the safety profile of these combinations, including their use in patients undergoing liver transplantation. Finally, we explore emerging opportunities and ongoing challenges in the field of precision immunotherapy and discuss future directions to improve clinical outcomes in patients with HCC.