Brain tumors, especially malignant gliomas and metastases, continue to pose serious clinical challenges due to their complex biology and limited treatment options. The traditional research paradigm mainly focuses on the tumor cells themselves and their interaction with the immune microenvironment, while the critical role of the nervous system (including neurons, glial cells, neurotransmitters/modulators, and nerve fibers) in the pathological process of tumors has been underestimated for a long time. This review systematically reviews breakthrough research in recent years, revealing that the nervous system plays an indispensable driving role in the development, proliferation, invasion, and treatment resistance of brain tumors. Specifically, neuronal activity profoundly influences tumor behavior through the utilization of direct "neuron-tumor synapses", neurotransmitter signaling (e.g., glutamate, γ-aminobutyric acid (GABA), neuropeptides), and axon-guiding molecules. At the same time, glial cells (astrocytes, microglia, etc.) undergo phenotypic remodeling in the tumor microenvironment, and their secretion products and functional status have complex regulatory effects on tumor progression. Conversely, the growth of brain tumors also violently reshapes the structure and function of the nervous system (such as the destruction of nerve fiber bundles) and function (such as inducing epilepsy, cognitive impairment, and neurological deficits), which involves multiple mechanisms such as neuroplasticity changes, neuroinflammation, metabolic competition, and neurovascular unit destruction. This broad and profound two-way interaction between the nervous system and brain tumors not only provides a new perspective for understanding the unique pathophysiology of brain tumors but also highlights its important clinical translational value as potential diagnostic markers and therapeutic targets. Tumordating the neural regulatory network from neurons to the entire tumor microenvironment will lay the foundation for the development of innovative therapeutic strategies targeting the "neuro-tumor axis", which is expected to break through the current bottleneck in brain tumor treatment.

Brain tumors, Nervous system, Tumor microenvironment, Neuron-tumor synapses, Neurotransmitters, Neuroglial cells, Targeted therapy