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From Carcinogenesis to Drug Resistance: The Multifaceted Role of Oxidative Stress in Head and Neck Cancer
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Curtin Medical School, Curtin University, Kent St, Bentley 6102, Australia
2
Curtin Medical Research Institute, Curtin University, Kent St, Bentley 6102, Australia
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Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 3030, Jordan
4
Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands 6009, Australia
5
Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(20), 3295; https://doi.org/10.3390/cancers17203295 (registering DOI)
Submission received: 18 September 2025
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Revised: 29 September 2025
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Accepted: 10 October 2025
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Published: 11 October 2025
(This article belongs to the Section Cancer Drug Development)
Simple Summary
Head and neck cancer is one of the most common cancers worldwide and is often linked to tobacco use, alcohol consumption, and certain viral infections. These factors increase harmful molecules called reactive oxygen species, which can damage cells but can also be used to destroy cancer cells. This review explores the dual role of these molecules in cancer—helping tumors grow in some cases, while also offering a way to eliminate cancer cells through treatment. We describe how cancer cells protect themselves from this damage by activating defense systems that can make them resistant to therapy. Understanding these mechanisms may guide the development of more effective future treatments that precisely target cancer cells, minimize side effects, and improve patient survival and quality of life.
Abstract
Objectives: This review examines the role of oxidative stress in the survival, apoptosis, and therapy resistance of head and neck squamous cell carcinoma (HNSCC) cells, with a focus on how redox imbalance influences tumour progression and treatment outcomes. Methods: A literature search was conducted in Scopus using the keywords head and neck squamous cell carcinoma, oxidative stress, reactive oxygen species (ROS), and antioxidant systems. Articles published in English were included, without restrictions on publication year. Reviews, clinical studies, and experimental research addressing oxidative stress mechanisms in HNSCC were considered, while non-English papers and studies unrelated to HNSCC were excluded. Key Findings: ROS exhibit dual effects in HNSCC, promoting tumour growth and DNA damage while also inducing apoptosis through molecular interactions. Elevated ROS contribute to drug resistance by inhibiting apoptosis, altering autophagy, and enhancing proliferation. Cancer cells counteract this via adaptive antioxidant responses involving transcriptional regulation and upregulation of enzymatic defences. Major risk factors for HNSCC—alcohol, tobacco, and high-risk HPV infection—disrupt redox homeostasis, underscoring the central role of oxidative stress in both carcinogenesis and therapy response. Conclusions: Oxidative stress plays a context-dependent role in HNSCC progression and treatment resistance. Targeting redox-regulatory pathways may provide therapeutic benefit. This review synthesizes recent insights on ROS-mediated mechanisms, highlighting potential strategies for improving HNSCC management beyond existing literature.
