Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities

The nervous system has emerged as an active regulator of the tumor ecosystem. Neural inputs from the central, peripheral, and enteric nervous systems influence tumor initiation, progression, metastasis, and therapeutic response through innervation and signal transmission. In addition to regulating tumor cell states, neural signaling reshapes stromal and immune compartments, promoting stemness, invasion, angiogenesis, metabolic adaptation, and immune evasion. Tumors, in turn, actively remodel their neural niche through neurogenesis, axonal remodeling, and tumor-nerve feedforward circuits. The biological effects of neuro-tumor crosstalk are highly context-dependent and are jointly determined by neural origin, receptor distribution, tumor state, and the local microenvironment. Accordingly, neural signaling has become a promising axis for therapeutic intervention. In this review, we summarize key advances in the molecular mechanisms of neuro-tumor communication over the past five years. We also highlight neurotransmitter and neuropeptide receptor axes with pharmacological and translational relevance, related targeted agents, and therapeutic strategies for targeting these pathways, as well as recent progress in neuro-immune combination therapy and clinical studies. Together, these advances provide an updated framework for understanding the role of neural signaling in tumor biology and its therapeutic potential.