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Purpose of Review <p>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.</p> Recent Findings <p>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.</p> Summary <p>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.</p>

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DNA Repair, Epigenetic Dysregulation, and Cytokine Network Crosstalk in Head and Neck Cancer: Emerging Therapeutic Opportunities and Clinical Trials

  • 期刊论文

  • 发表日期：

    2026年7月25日

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  • Nistha Agarwal,
  • Garima Sharma,
  • Ashish Ranjan Sharma,
  • Vinod Kumar Gupta,
  • Yuyuan Guo,
  • Abhimanyu Kumar Jha,
  • Jin-Chul Kim

摘要

Purpose of Review

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 Findings

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.

Summary

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.