Mechanism-guided radiosensitization strategies for nasopharyngeal carcinoma: Current evidence and translational...

Nasopharyngeal carcinoma (NPC) is a distinct Epstein-Barr virus (EBV)-associated head and neck malignancy with a pronounced endemic distribution in Southern China and Southeast Asia. Intensity-modulated radiotherapy and concurrent chemoradiotherapy (CCRT) have substantially improved locoregional control; however, treatment failure remains common, particularly in locoregionally advanced, recurrent and metastatic disease. The present review summarizes mechanism-guided radiosensitization strategies for NPC according to clinical setting and translational maturity. Platinum-based CCRT remains the standard and most established radiosensitization approach. In selected patients with locoregionally advanced disease and a suboptimal response to induction chemotherapy, the addition of nimotuzumab to CCRT did not improve 2-year progression-free survival (81.0 vs. 80.8%; hazard ratio=0.93). By contrast, tislelizumab combined with chemotherapy markedly improved progression-free survival in recurrent or metastatic disease (hazard ratio=0.52), highlighting that systemic efficacy in this setting should not be conflated with radiosensitization during definitive radiotherapy. Consequently, epidermal growth factor receptor inhibition, DNA damage response targeting, hypoxia modification, immunoradiotherapy and EBV-directed therapies remain dependent on appropriate patient selection and prospective validation. Natural compounds and traditional Chinese medicine-derived agents are mechanistically promising but currently remain hypothesis-generating. Collectively, these approaches converge on key biological processes, including DNA repair, oxidative stress, apoptosis, epithelial-mesenchymal transition, hypoxia, EBV-associated signaling and immune remodeling. Plasma EBV DNA is currently the biomarker with the greatest clinical readiness for risk stratification, whereas most predictive biomarkers remain investigational. Key challenges include heterogeneous evidence quality, uncertain treatment sequencing and overlapping toxicities. Future treatment intensification should be biomarker-informed and tailored to disease stage, patient fitness and therapeutic index.