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DNA Repair, Epigenetic Dysregulation, and Cytokine Network Crosstalk in Head and Neck Cancer: Emerging Therapeutic Opportunities and Clinical Trials
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DOI：10.1007/s11912-026-01808-0.png)
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Abstract
En 中文
Head and neck cancer (HNC) is characterized by profound genomic instability, therapeutic resistance, and suboptimal survival outcomes, particularly in advanced-stage disease. This review aims to critically examine the mechanistic interplay between DNA damage response (DDR) pathways, epigenetic dysregulation, and cytokine-driven inflammatory networks, and to evaluate their collective impact on HNC progression and therapeutic vulnerability. Recent studies have demonstrated that defects in DDR pathways contribute to genomic instability and activate cytosolic DNA sensing via the cGAS-STING pathway, leading to type I interferon production and modulation of the tumor microenvironment. In addition, epigenetic alterations influence DNA repair mechanisms and immune responses. Cytokine networks involving IL-6, TNF-α, and NF-κB/STAT3 signaling play a central role in tumor progression, immune evasion, and therapy resistance. Combination therapies, including PARP/ATR inhibitors with immune checkpoint blockade and cytokine-targeting agents, have shown promising results in preclinical and early clinical studies. The intricate crosstalk among DDR deficiency, epigenetic alterations, and inflammatory signaling constitutes a central axis in HNC pathobiology and therapeutic resistance. Targeting these interconnected pathways through rational combination strategies offers a promising avenue to enhance treatment efficacy and advance precision oncology. Continued integration of molecular profiling and biomarker-driven approaches will be essential to optimize patient stratification and improve clinical outcomes in HNC.
Keywords:
Head and neck cancer (HNC)
DNA damage response (DDR)
Epigenetic alterations
Genomic instability
PARP inhibitors
Precision oncology
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