Neural-tumor interactions: bidirectional regulatory mechanisms and nervous system-targeted tumor therapeutic strategies.

Neural-tumor crosstalk has emerged as a critical frontier in tumor microenvironment research. Central to this field is the dynamic, bidirectional regulatory network between the nervous system and tumor cells that orchestrates malignant progression. This review focuses on tumors arising outside the central nervous system and their bidirectional interactions with peripheral nerves, summarizing the current evidence on the molecular mechanisms underlying these reciprocal interactions. We first examine how neural components modulate tumorigenesis through the release of neuroactive molecules and proteins that activate oncogenic signaling pathways. In particular, neurons and Schwann cells can transmit protumorigenic signals via paracrine signaling, exosome-mediated communication, and the formation of functional neuroneoplastic synapses. Conversely, tumors can actively "hijack" and remodel their neural architecture to promote axonogenesis and neural infiltration while contributing to complications such as cancer pain and paraneoplastic neurological syndromes. We further highlight the pivotal role of neural signaling in reshaping the tumor microenvironment across three interconnected dimensions: the spatial dimension (neural niches), the signaling dimension (bidirectional communication mediated by neuroactive molecules), and the functional dimension (immunometabolic reprogramming). Together, these processes contribute to tumor progression and immune evasion. Building on these insights, therapeutic strategies targeting the neural-tumor interface have shown promising clinical potential. Further characterization of these regulatory networks may identify context-specific drivers of tumorigenesis and progression and inform the development of novel therapeutics targeting neural pathways.