Neural regulation of cancer: from synaptic integration to neuro-immune regulation

The emerging field of cancer neuroscience has reshaped our understanding of tumor biology, showing that the nervous system is an active participant in the tumor microenvironment. It modulates tumor progression through synaptic communication with cancer cells, paracrine signaling via neurotransmitters and neuropeptides, and indirect regulation of the tumor immune microenvironment. Recent discoveries have shown that neurons form synapses with brain tumors and peripheral cancers, driving tumor cell proliferation and invasion. Neurotransmitter and neuropeptide signaling activates pathways in cancer cells to promote malignancy. Furthermore, the nervous system shapes anti-tumor immunity by modulating T cells, natural killer cells, macrophages, and myeloid-derived suppressor cells, creating either an immunostimulatory or, more commonly, an immunosuppressive microenvironment that facilitates immune evasion and treatment resistance. The clinical significance of the neuro-immune-tumor axis is confirmed across multiple cancer types. Consequently, therapeutic strategies targeting neural regulation are emerging, including neurotransmitter receptor blockers, denervation techniques, neuromodulation devices, and approaches to remodel the immune landscape through neural signals. This review synthesizes how nerves regulate tumor progression via synaptic connections, neurotransmitter release, and immune modulation. We also summarize current and emerging therapeutic strategies aimed at disrupting or harnessing neuro-tumor communication. By integrating recent advances, this review aims to establish a framework for understanding neural regulation of cancer and to guide future research and clinical translation in this evolving field.