The role of N6-methyladenosine (m6A) modification in the development and progression of head and neck squamous cell carcinoma (HNSCC): mechanistic insights and translational challenges

Abstract

Head and neck squamous cell carcinoma (HNSCC) ranks as the sixth most prevalent malignancy worldwide, encompassing tumors derived from the mucosal epithelia of the oral cavity, pharynx, larynx and other head and neck regions. Most patients are diagnosed at an advanced stage due to limited early screening tools and nonspecific initial symptoms, a situation that correlates with a poor prognosis, high rates of local recurrence and distant metastasis, and low overall survival (OS). This grim clinical status underscores the urgent need to clarify the molecular mechanisms driving HNSCC initiation and progression and to develop novel targeted therapeutic strategies. In recent years, advances in epigenetic research technologies, such as high-throughput sequencing and mass spectrometry-based detection, have drawn increasing attention to N6-methyladenosine (m6A) modification and its associated m6A-binding proteins in HNSCC. As the most common and well-characterized internal post-transcriptional modification in eukaryotic messenger RNA (mRNA), m6A is dynamically regulated by a network of "writers," "erasers," and "readers." This network modulates RNA metabolism, including splicing, stability, and translation—further regulating gene expression in a context-dependent manner. Accumulating in vitro and in vivo evidence demonstrates that m6A regulators modulate the proliferation, migration, invasion, epithelial–mesenchymal transition (EMT) and immune evasion of HNSCC cells by altering m6A modification levels of key oncogenes and tumor suppressor genes. Despite the recognized role of m6A as a critical epigenetic regulator in HNSCC, a synthesis that simultaneously incorporates HNSCC subsite heterogeneity, human–papillomavirus (HPV) status stratification, and evidence-graded evaluation of translational potential remains limited. This review provides a subsite-aware and translationally focused synthesis of the available evidence, with a particular emphasis on HPV status, immune regulation, and the context-dependent functions of m6A regulators in HNSCC. We systematically summarize the roles of m6A writers, erasers, and readers in HNSCC subtype-specific biology, critically evaluate the translational prospects of m6A-related biomarkers and therapeutic targets, acknowledging the current evidence limitations and the need for prospective validation, and propose a phased roadmap from mechanistic insights to clinical application. It should be emphasized that most of the evidence discussed in this review remains preclinical, and no m6A-targeted therapy has been validated for clinical use in HNSCC to date.