Neural-tumor crosstalk in driving tumor metabolic reprogramming

Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.