Challenges and Strategies of Non-Coding RNA Therapies in Addressing Tumor Heterogeneity in Head and Neck Cancers.

Head and neck cancer (HNC) exhibits significant heterogeneity, leading to variable treatment responses and unstable efficacy of non-coding RNA (ncRNA) therapies, which presents a major challenge in clinical management. ncRNAs, including miRNAs, lncRNAs, and circRNAs, play pivotal roles in regulating tumor initiation, progression, and drug resistance. However, their expression and function are dynamically reshaped by tumor heterogeneity, thereby compromising the stability and predictability of ncRNA-based therapies. This article first systematically reviews the current research landscape of different ncRNAs in HNC at the molecular level. It further explores the challenges posed by heterogeneity in ncRNA therapy concerning delivery, target selection, and microenvironmental interference. Subsequently, it summarizes various countermeasures and future directions, including those based on precision diagnostics, novel delivery systems, gene editing technologies, and multimodal combination strategies. Finally, the article prospects the application potential of individualized ncRNA treatment strategies that integrate heterogeneity information in the future of precision medicine for HNC.