Integrating Radiotherapy and Systemic Therapy in Hepatocellular Carcinoma: From Biological Rationale to Clinical Evidence

The therapeutic landscape of hepatocellular carcinoma (HCC) has evolved with advances in systemic therapy and radiotherapy. Immune-checkpoint inhibitors, anti-angiogenic agents, stereotactic body radiotherapy (SBRT), and yttrium-90 transarterial radioembolization (TARE) have expanded treatment options across multiple stages of disease. Radiotherapy may complement systemic therapy through biological interactions involving tumor vasculature, hypoxia, and the immune microenvironment. These observations have generated growing interest in combined-modality therapy, although optimal approaches continue to be defined. In this review, we summarize the biological rationale and clinical evidence for integrating SBRT or TARE with targeted and immunotherapy-based regimens. We also highlight ongoing trials and emerging strategies for biologically informed therapy sensitization targeting tumor and immune-cell biology.