Tumour – nerve interactions in oral squamous cell carcinoma: Mechanisms, clinical implications, and emerging therapeutic targets

Abstract

Tumour–nerve interactions have emerged as a critical yet underexplored component of cancer biology, particularly in oral squamous cell carcinoma (OSCC). Beyond traditional paradigms cantered on tumour size and stage, accumulating evidence demonstrates that neural elements actively contribute to tumour initiation, progression, invasion, and symptomatology. This review synthesizes current understanding of tumour–nerve crosstalk in OSCC, focusing on perineural invasion (PNI), tumour-induced neurogenesis, and neurotransmitter-mediated signalling pathways. These interactions not only drive tumour aggressiveness and metastatic potential but also underpin characteristic pain syndromes, especially neuropathic pain. Clinically, PNI is associated with adverse outcomes, including increased recurrence and reduced survival, while emerging evidence suggests that pain characteristics may serve as early indicators of neural involvement. Advances in neurotrophic signalling pathways, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), have opened new avenues for targeted therapeutic intervention. Integrating tumour–nerve biology into clinical practice may enhance early diagnosis, prognostication, and treatment strategies. This review highlights tumour–nerve interactions as a novel framework for understanding OSCC and underscores the need for further translational research.