Neuronal regulation of cancer: Mechanisms, functional consequences and therapeutic opportunities

Recent breakthroughs highlight a previously underappreciated role of the nervous system in tumor biology, drawing attention to the emerging interdisciplinary field of tumor neuroscience. Foundational discoveries have elucidated complex bidirectional interactions between neurons and cancer cells, redefining the tumor microenvironment as a dynamic neurobiological niche. A major recent breakthrough is the discovery that tumor cells can form direct synaptic or pseudo-synaptic contacts with neurons, extending the concept of synaptic communication beyond the nervous system. In this Review, we summarize current knowledge of neuronal regulation in cancer across three layers: direct synaptic communication, neuron-derived paracrine signaling, and neuroimmune modulation. We further discuss the functional consequences of these interactions, including perineural invasion, tumor-associated epilepsy and cancer pain, together with emerging therapeutic strategies targeting tumor-neuron crosstalk, highlighting these overlooked therapeutic opportunities for highly aggressive tumors. Finally, we propose a translational framework to bridge basic discoveries with clinical application.