The neuro-immune-tumor axis in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) remains a therapeutic challenge characterized by high locoregional recurrence and resistance to conventional treatments. While the nervous system was historically regarded as a passive victim of tumor invasion, the emerging field of cancer neuroscience has redefined nerves as active architects of the tumor microenvironment (TME). This review explores the neuro-immune-tumor axis in HNSCC, a malignancy uniquely situated in an anatomical region densely innervated by cranial nerves. We synthesize current evidence demonstrating that perineural invasion (PNI) is not merely a path of spread but a bidirectional signaling pathway driven by neurotrophic factors and Schwann cell reprogramming. Crucially, we highlight the immunosuppressive role of neural signaling. Sensory nerves releasing CGRP, and sympathetic fibers secreting norepinephrine synergistically inhibit CD8 + T cell function and promote macrophage M2 polarization, creating a neuro-immune barrier to therapy. Furthermore, we discussed the systemic impact of this axis, including the influence of chronic stress via hypothalamic-pituitary-adrenal (HPA) axis and oral-gut-brain axis. Finally, we explored the clinical implications of these findings, proposing that targeting neural signaling, through drug repurposing or neuro-immunotherapy combinations, represents a promising strategy to overcome the immunosuppressive TME and improve patient outcomes in HNSCC.