Abstract
Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy with a persistently high mortality rate, largely attributable to therapy resistance and tumor recurrence. This review comprehensively explores the critical interplay between epigenetic dysregulation and the tumor microenvironment (TME) in driving OSCC progression. We detail how key epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), intrinsically transform cancer cells and actively orchestrate pro-tumorigenic TME. These alterations substantially contribute to resistance against conventional therapies. Furthermore, we discuss the therapeutic potential of targeting these pathways using epigenetic drugs (epi-drugs), such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, as well as engineered extracellular vesicles (EVs). The primary objective of this review is to synthesize current knowledge on the epigenetic-TME axis, thereby providing a mechanistic foundation for developing novel therapeutic strategies. We emphasize that rational combinations of epigenetic-targeting agents with conventional treatments or immunotherapy hold significant promise for overcoming drug resistance and improving clinical outcomes in OSCC patients.