Decoding the role of non-coding RNAs in HNSCC radioresistance: molecular mechanisms and clinical implications.

Head and neck squamous cell carcinomas (HNSCC) are the sixth most commonly diagnosed cancer globally, with a stagnant five-year survival rate of approximately 50%. Risk factors include human papillomavirus (HPV) infection, smoking, alcohol consumption, and betel nut chewing, contributing to its genetic and molecular heterogeneity. Although radiotherapy is a primary treatment modality for locally advanced or inoperable HNSCC, the inherent radioresistance of tumor tissues limits its effectiveness, emphasizing the need for strategies to enhance radiosensitivity. Emerging evidence highlights the critical role of non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in regulating tumor radiosensitivity by modulating cell cycle, DNA damage response (DDR), cell proliferation, invasion, and migration. This review systematically examines the molecular mechanisms and clinical significance of ncRNAs in the radioresistance of HNSCC, summarizing 118 ncRNAs (from 103 articles), including 31 radioresistant miRNAs, 51 radiosensitive miRNAs, 22 radioresistant lncRNAs, 4 radiosensitive lncRNAs, 7 radioresistant circRNAs, and 3 radiosensitive circRNAs. Furthermore, this study discusses the potential roles of ncRNAs, specifically their use as predictive biomarkers for response to radiotherapy and as therapeutic targets in precision oncology. By integrating molecular insights with clinical perspectives, this review provides a valuable framework for understanding ncRNA-mediated radioresistance and proposes new strategies to overcome the challenges in improving HNSCC treatment.