From Carcinogenesis to Drug Resistance: The Multifaceted Role of Oxidative Stress in Head and Neck Cancer

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.