From Environmental Risk to Cancer Stemness: Epigenetic Regulation in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) represents a major global health burden and remains one of the most prevalent and aggressive malignancies of the head and neck region. Despite significant advances in surgical techniques, chemotherapy, and radiotherapy, patient outcomes have improved only modestly over recent decades. The high recurrence rate, metastatic potential, and resistance to therapy underscore the complexity of OSCC biology and the limitations of conventional treatment approaches. In recent years, the concept of cancer stem cells (CSCs) has reshaped the understanding of tumor initiation, progression, and therapeutic failure in OSCC. These cells, characterized by self-renewal capacity and phenotypic plasticity, are believed to sustain tumor growth, drive recurrence, and mediate resistance to therapy. Parallel to this, insights into epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, have revealed new layers of molecular heterogeneity and adaptability in oral carcinogenesis. The integration of CSC biology with epigenetic modulation offers a promising foundation for the development of targeted and personalized therapeutic strategies. Novel approaches aim to eradicate CSCs, induce their differentiation, or reprogram their malignant phenotype through the use of epigenetic inhibitors and molecular modulators. This review summarizes current knowledge on the molecular and cellular mechanisms driving OSCC pathogenesis, highlights the emerging role of CSCs and epigenetic regulators, and discusses the challenges and perspectives of translating these findings into effective clinical therapies.