Interplay Between Glutamine Metabolism and Other Cellular Pathways: A Promising Hub in the Treatment of HNSCC

Head and neck squamous cell carcinoma (HNSCC) is the most common and aggressive histologic subtype of head and neck cancer (HNC), difficult to treat effectively. Here, we discuss several studies on human and mouse HNSCC cell lines arising from the mucosal epithelium of various anatomical sites, as well as recent studies using murine models, focused on targeting key checkpoints in the glutamine (Gln) metabolism pathway, either alone or in synergy with other signaling pathways, as a potential therapeutic strategy for HNSCC. Emerging evidence demonstrates a complex interplay between Gln metabolism and pathways mediating altered cellular mechanisms, including ferroptosis, immune system evasion, mitochondrial energy production, and oncogenic transcriptional control. This review examines currently available gene expression databases and protein expression analyses of Gln metabolism-related components in tissue samples from HNSCC patients. From a translational perspective, the co-administration of pharmaceutical agents and biologic products targeting distinct molecular pathways, integrated with radiotherapy (RT) or chemotherapy (CT), may produce superior anti-HNSCC efficacy, thereby improving clinical outcomes and extending patient survival. Multimodal strategies represent a key direction in precision oncology, enabling personalized therapeutic interventions to suppress metastatic dissemination and disease progression more effectively. Therefore, an integrated therapeutic approach represents a promising path to defeat HNSCC.