Radiosensitization strategies for hepatocellular carcinoma: Mechanisms, therapeutic advances, and clinical perspectives

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with treatment efficacy limited by late-stage diagnosis, frequent recurrence, and therapeutic resistance. Radiotherapy is a key local treatment for HCC; however, its efficacy is frequently limited by intrinsic tumor radioresistance. This review discusses strategies to improve the therapeutic response of HCC to radiotherapy. Targeting DNA repair mechanisms can block tumor cells from recovering after radiation-induced damage, whereas modulating cell cycle arrest and programmed cell death pathways (e.g., apoptosis, autophagy) diminishes their survival capacity. Furthermore, remodeling the tumor microenvironment—through hypoxia alleviation, metabolic reprogramming, oxidative stress regulation, and immune activation—may potentiate radiotherapy efficacy. Technological advances, such as stereotactic body radiotherapy and nanomaterial-based approaches, have also improved the precision and effectiveness of radiotherapy. Clinically, combining radiotherapy with systemic therapies (e.g., immune checkpoint inhibitors and antiangiogenic agents) has demonstrated preliminary promise in enhancing treatment outcomes. However, translating preclinical findings into clinical practice remains challenging due to tumor heterogeneity, normal tissue toxicity, and the lack of predictive biomarkers for treatment selection. Future research should focus on integrating molecular profiling with multimodal therapies to enable personalized radiosensitization and bridge the gap between mechanistic insights and clinical outcomes.