The glycolysis–neurotransmitter axis: a missing link in head and neck squamous cell carcinoma biology

Head and neck squamous cell carcinoma remains a major clinical challenge because of its high rates of recurrence, metastasis, and therapeutic resistance despite advances in treatment. Enhanced glycolysis and neurotransmitter signalling are independently recognised as key drivers of tumour progression; however, their mechanistic relationship remains poorly understood, highlighting the need for an integrated framework that explains how metabolic reprogramming influences neural signalling in tumour progression. Building on the established fields of cancer metabolism and cancer neuroscience, we propose a focused, HNSCC-specific extension of these frameworks: aberrant glycolytic reprogramming is hypothesised to function as a key upstream regulator of neurotransmitter remodelling, contributing to tumour progression, immune evasion, and therapeutic resistance. To keep the model testable, we narrow our primary focus to the lactate–HIF-1α–GPR81–NGF/BDNF axis and its influence on adrenergic (sympathetic) signalling, treating cholinergic and glutamatergic contributions as secondary, exploratory components. Glycolysis-induced metabolic alterations, including lactate accumulation, intracellular metabolite availability, and tumour microenvironment acidification, are hypothesised to regulate neurotransmitter synthesis, release, and receptor-mediated signalling, creating a self-reinforcing neuro-metabolic feedback loop that enhances tumour aggressiveness, although non-metabolic drivers such as autonomic nerve activity and psychological stress are also acknowledged as potential contributors to this signalling. This hypothesis can be evaluated using complementary molecular, cellular, and translational approaches by correlating glycolytic activity with neurotransmitter expression and assessing the biological consequences of glycolytic modulation; quantification of glycolytic markers and neurotransmitter profiles, together with functional analyses and clinical correlation studies, would determine whether glycolysis acts as an upstream regulator of neurotransmitter remodelling in head and neck squamous cell carcinoma. The proposed glycolysis–neurotransmitter axis thus provides a biologically plausible and experimentally testable framework that integrates metabolic and neural mechanisms in this cancer; if validated, this model could offer preliminary support for metabolism-associated neurotransmitter biomarkers and help inform future, rigorously validated metabolism-directed therapeutic strategies; such translational applications remain speculative and contingent on further experimental and clinical validation.