Cancer Stem Cell Mechanisms and Targeted Therapeutic Strategies in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) originates in the epithelial lining of the oral cavity, pharynx, and larynx, with over 830,000 new cases diagnosed globally in 2020, making it the seventh most prevalent cancer. Despite treatment advances, high-grade HNSCCs remain associated with poor outcomes and a high risk of recurrence. Although Cancer Stem Cells (CSCs) are rare in HNSCC tumors, they are key drivers of tumor relapses, as they evade apoptosis and survive current therapies through enhanced DNA repair and quiescence. This review integrates recent discoveries into a unified framework for understanding CSC mechanisms. It examines the role of pluripotency factors, biomarkers, replicative immortalization, metabolic reprogramming, redox regulation, and immune evasion in shaping CSC behavior and survival under treatment stress. Non-coding RNAs are also discussed as modulators of gene expression via epigenetic regulation in CSCs. Importantly, it highlights how these adaptive mechanisms intersect as potential vulnerabilities that could be exploited to eliminate CSCs through targeting multiple pathways. Finally, it provides recent and emerging precision therapeutics, including CAR-T cells, immune checkpoint inhibitors, metabolic and redox-targeting agents, and epigenetic modulators currently in preclinical and clinical trials applications designed to eliminate CSCs and improve patient outcomes in HNSCC.