Evolving Landscape of Systemic Therapy for Hepatocellular Carcinoma in 2025

Hepatocellular carcinoma (HCC), the sixth most common malignant tumor, accounts for approximately 90% of liver cancers. HCC is frequently diagnosed at an advanced stage, where systemic therapy becomes the primary treatment option. As understanding about the molecular signaling pathways within tumors and the tumor microenvironment have evolved, treatment option for advanced HCC has also become more innovative. Current therapies target cellular pathways, including tyrosine kinase inhibitors (TKIs) like lenvatinib, sorafenib, regorafenib, and cabozantinib, which disrupt signals crucial for tumor growth and survival; VEGF (vascular endothelial growth factor) inhibitors that block tumor blood vessel formation; and immunotherapy agents such as atezolizumab-bevacizumab, tremelimumab, and durvalumab, which stimulate the immune system to attack cancer cells. Both targeted therapies and immunotherapies, used alone or in combination, have demonstrated efficacy in clinical trials. The treatment landscape for HCC is rapidly evolving, driven by recent landmark trial results exploring innovative strategies and drug combinations. This review examines these exciting advancements in systemic therapy, highlighting their transformative potential and the promise of more effective, personalized treatment regimens. These developments offer hope for improved patient outcomes and a deeper understanding of this complex disease.