REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicEpigenetic Alterations in Tumors and Therapeutic ResistanceView all 8 articles
Dissecting the role of epigenetic regulation in oral squamous cell carcinoma microenvironment: mechanisms and therapeutics
Provisionally accepted
- 1Jilin University Stomatology Hospital, Changchun, China
- 2Yale University Yale Cancer Center, New Haven, United States
- 3Yale School of Medicine, New Haven, United States
- 4Philipps-Universitat Marburg, Marburg, Germany
- 5China-Japan Union Hospital, Jilin University, Changchun, China
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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.
Keywords: biomarkers, Epigenetic regulation, oral squamous cell carcinoma, therapeutic targets, Tumor Microenvironment
Received: 01 Dec 2025; Accepted: 02 Jan 2026.
Copyright: © 2026 Li, Ren, Pei, Zhao, Chen and He. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Guan-yu Chen
Zhenglin He
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