Breaking Barriers in Hepatocellular Carcinoma: Synergistic Potential of Stereotactic Body Radiotherapy Combined With...

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with limited long-term survival for patients presenting with advanced or unresectable disease. While immune checkpoint inhibitors (ICIs) and antiangiogenic agents have expanded systemic treatment options, therapeutic efficacy is frequently constrained by tumor heterogeneity, immune resistance, and underlying liver dysfunction. Stereotactic body radiotherapy (SBRT), beyond providing high local tumor control, has emerged as a potent immune-modulating modality capable of reshaping the tumor microenvironment and enhancing systemic antitumor immunity. These biological effects have catalyzed growing interest in integrating SBRT with immunotherapy and antiangiogenic agents as a multimodal strategy to overcome immune resistance in advanced HCC.

This review critically examines the evidence, mechanisms, and clinical impact of integrating SBRT with ICIs and antiangiogenic therapies for advanced HCC. It highlights gaps in current knowledge and explores strategies for optimizing combination treatment, particularly in challenging subsets such as portal vein tumor thrombosis (PVTT) and extrahepatic metastases.

Clinical evidence suggests that triple-combination therapy-SBRT with ICIs and antiangiogenic agents-offers marked survival advantages over single or dual regimens. Median overall survival and progression-free survival nearly double compared to dual therapy, while response rates surpass 60% with disease control approaching 100%. Complementary mechanisms underpin these gains: SBRT induces immunogenic cell death and antigen release, ICIs reinvigorate exhausted T cells, and vascular endothelial growth factor (VEGF) inhibition normalizes tumor vasculature to facilitate immune infiltration. Notably, the benefit extends to high-risk groups, such as those with portal vein tumor thrombosis, where survival outcomes remain superior to those of alternative treatments. Safety profiles appear acceptable, with no excess of severe toxicities.

The synergistic integration of SBRT, ICIs, and antiangiogenic agents represents a transformative advancement in HCC therapy, achieving superior survival, tumor control, and manageable safety profiles. Further investigation is necessary to refine patient selection, optimize protocols, and validate the long-term efficacy of this triple-combination regimen, thereby establishing it as a standard of care in the management of advanced HCC.