Disarming the “Neural Hijack”: Repurposing neuroactive drugs for cancer therapy

The emerging field of cancer neuroscience has fundamentally reshaped our understanding of malignancy, revealing tumors as complex ecosystems deeply integrated with and actively shaped by the nervous system. Malignancies recruit, reprogram, and exploit neural components, a phenomenon we conceptualize as "neural hijack" to fuel growth, metastasis, immunosuppression, and therapy resistance. Concurrently, drug repurposing, leveraging the established safety profiles of approved neuroactive agents, has emerged as a powerful strategy to therapeutically dismantle this tumor-neural axis. This review synthesizes the neural hijack paradigm, detailing how cancers co-opt neuropeptide, neurotransmitter, and synaptic signaling pathways. We provide a comprehensive evaluation of repurposed neuroactive drugs, including β-blockers, CGRP antagonists, NK1R antagonists, SSRIs, and anti-epileptics, framing their mechanisms within the disruption of specific hijacking nodes. We further propose "neural signatures", composite biomarkers integrating innervation density, receptor profiles, and neuro-immune contexture as critical tools for precision patient stratification. Finally, we discuss translational challenges and innovative solutions, charting a roadmap toward "neural disconnection", the therapeutic severing of the tumor's neural lifeline, as an emerging pillar of cancer therapy.