Abstract
Recent breakthroughs in tumor biology have redefined the tumor microenvironment as a dynamic ecosystem in which the nervous system has emerged as a pivotal regulator of oncogenesis. In addition to their classical developmental roles, neural‒tumor interactions orchestrate a sophisticated network that drives cancer initiation, stemness maintenance, metabolic reprogramming, and therapeutic evasion. This crosstalk operates through multimodal mechanisms, including paracrine signaling, electrophysiological interactions, and structural innervation guided by axon-derived guidance molecules. Key discoveries reveal that tumors actively recruit and remodel local neurons, hijacking neurodevelopmental pathways to foster invasive growth. Moreover, malignant cells exhibit neuronal-like plasticity, adopting electrophysiological properties that increase survival under therapeutic stress. These findings position neural mimicry as a hallmark of aggressive cancers. The expanding field of cancer neuroscience seeks to unravel the essential signaling factors that drive the complex communication between cancer and the nervous system, utilizing these findings to enhance precision therapies for cancer management. In this Review, we highlight considerable advancements in cancer neuroscience studies, sparking further discussions on various research possibilities and outlining a direction for future investigations. Additionally, we explored promising therapeutic strategies rooted in neural-tumor interactions that could synergize with conventional standard treatments, offering renewed therapeutic vigor for many refractory malignancies.