Neuron-tumor crosstalk in cancer: molecular mechanisms and translational advances

Tumor neuron hijack is a malignant adaptive program whereby tumor cells recruit, physically engage and functionally reprogram the peripheral and central nervous system within the local microenvironment and host macroenvironment; this process not only exploits neuro-immune regulatory machineries, neural endocrine signaling, and nutrient supply for sustaining tumor growth, invasion, metastasis, immune escape and treatment resistance, but also closely involves the induction and amplification of cancer-associated pain, a common and debilitating manifestation of the host's pathological response to tumor-neural crosstalk, which further perturbs the host macroenvironment and facilitates tumor progression. Neoplastic cells employ context-dependent strategies: central nervous system tumors (e.g., gliomas) integrate into existing neuronal circuits via synaptogenesis and metabolic coupling, while peripheral solid tumors induce de novo innervation via neurotrophic factors, axon guidance cues regulating angiogenesis, and perineural invasion. Sympathetic, parasympathetic, and sensory nerves modulate tumor behavior via neurotransmitters or neuropeptides, with autonomic nerves also regulating endocrine glands to reprogram tumor metabolism. Pivotal to this regulation is the tripartite crosstalk among nerves, immune cells, and tumor cells, which establishes an immunosuppressive tumor microenvironment and drives progression from immune equilibrium to escape. These mechanisms have spurred therapeutic avenues such as neurotrophic agent repurposing, synaptic blockade, and neural-signal reprogramming, particularly in combination with immunotherapy, with promising preclinical and translational potential for precision oncology and cancer pain management.