Interplay between hypoxia, RNA methylation, and HPV in head and neck squamous cell carcinomas: drivers of oncogenesis and resistance to therapy

Authors

  • Marcel Mohr Doctoral School of Molecular Medicine, Medical University of Lodz, Haller Square 1, 90-624 Lodz, Poland; Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0009-0002-9294-1336
  • Julia Kozikowska Department of Head and Neck Surgery, Poznan University of Medical Sciences, Garbary 15 Street, 61-866 Poznan, Poland; Master Student at Adam Mickiewicz University, Uniwersytetu Poznańskiego 6 Street, 61-614 Poznan Poznan, Poland; Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0009-0007-3373-2768
  • Zuzanna Petryszyn Department of Molecular Biology and Genetics, Aarhus University, Nordre Ringgade 1, 8000 Aarhus Centrum, Denmark; Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0009-0006-4522-2629
  • Kamila Ostrowska Department of Head and Neck Surgery, Poznan University of Medical Sciences, Garbary 15 Street, 61-866 Poznan, Poland; Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0000-0002-4417-1579
  • Ewelina Golusińska-Kardach Department of Dental Surgery, Periodontology and Oral Mucosa Diseases, Poznan University of Medical Sciences, Bukowska 70 Street, 60-812 Poznan, Poland https://orcid.org/0000-0002-9520-2670
  • Wojciech Golusiński Department of Head and Neck Surgery, Poznan University of Medical Sciences, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0000-0002-6075-3464
  • Wiktoria Suchorska Department of Electroradiology, Poznan University of Medical Sciences, Fredry 10 Street, 61-701 Poznan, Poland; Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland https://orcid.org/0000-0003-4742-2465
  • Katarzyna Kulcenty Radiobiology Laboratory, Greater Poland Cancer Centre, Garbary 15 Street, 61-866 Poznan, Poland. Tel: +48 618 850 476, E-mail: katarzyna.kulcenty@wco.pl https://orcid.org/0000-0001-8400-249X

DOI:

https://doi.org/10.17179/excli2025-8834

Keywords:

head and neck squamous cell carcinoma, human papilloma virus, N6-Methyladenosine (m6A) RNA modification, hypoxia, immunotherapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) encompasses a diverse group of tumors with varying etiology, biology, and response to therapy. Among its subtypes, human papillomavirus positive HNSCC is associated with better prognosis and enhanced sensitivity to radiotherapy, chemotherapy, and immunotherapy. However, resistance still occurs and is often driven by complex molecular mechanisms that remain incompletely understood. Recent evidence highlights the pivotal role of RNA modifications—particularly N6-methyladenosine (m⁶A)—in regulating key processes such as gene expression, immune response, and treatment resistance. Dysregulation of m⁶A machinery, including methyltransferases (METTL3, METTL14), demethylases (FTO, ALKBH5), and m⁶A readers (YTHDFs, IGF2BPs), has been implicated in oncogenesis, immune evasion, and therapy failure in multiple cancers, including HNSCC. These epitranscriptomic changes intersect with hypoxia-driven signaling pathways, which reshape the tumor microenvironment, promote immunosuppression, and impair DNA repair, further contributing to resistance to conventional and targeted therapies. Moreover, in HPV-related HNSCC, viral oncoproteins modulate both RNA methylation and host immune dynamics, creating a unique biological context where m⁶A modifications may serve as mediators of HPV-specific oncogenic programs and therapeutic vulnerabilities. This review integrates current knowledge on the interplay between hypoxia, m⁶A RNA methylation, and HPV infection in HNSCC, emphasizing their combined role in shaping tumor progression and resistance. A deeper understanding of these pathways may offer new opportunities for biomarker discovery and the development of rational combination therapies.

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Published

2025-12-10

How to Cite

Mohr, M., Kozikowska, J., Petryszyn, Z., Ostrowska, K., Golusińska-Kardach, E., Golusiński, W., … Kulcenty, K. (2025). Interplay between hypoxia, RNA methylation, and HPV in head and neck squamous cell carcinomas: drivers of oncogenesis and resistance to therapy. EXCLI Journal, 24, 1767–1796. https://doi.org/10.17179/excli2025-8834

Issue

Vol. 24 (2025)

Section

Review articles

Categories

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Copyright (c) 2025 Marcel Mohr, Julia Kozikowska, Zuzanna Petryszyn, Kamila Ostrowska, Ewelina Golusińska-Kardach, Wojciech Golusiński, Wiktoria Suchorska, Katarzyna Kulcenty

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