Neural regulation of cancer: from microenvironmental hijacking to systemic circuit co-option

The nervous system is increasingly recognized as an active regulator of tumor biology rather than a passive mediator of cancer-associated symptoms. Growing evidence supports a hierarchical framework of neuro-tumor interactions encompassing chemical, structural, and electrical levels, through which bidirectional communication influences tumor initiation, progression, metastasis, and therapeutic response. At the chemical level, neurotransmitters and neuropeptides regulate tumor cell proliferation, invasion, immune modulation, and stemness. At the structural level, neurogenesis and tumor-nerve interface coupling establish physical connectivity between nerves and cancer cells. At the electrical level, synapse-like communication, defined as functional signaling between neurons and tumor cells that resembles synaptic transmission in terms of directionality and signaling dynamics, enables direct regulation of tumor behavior by neuronal activity. Neural regulation exhibits pronounced context dependency, with both tumor-promoting and tumor-suppressing effects depending on tumor type, genetic background, and microenvironmental context, as exemplified in pancreatic ductal adenocarcinoma, melanoma, and breast cancer. At the systemic level, neural circuits regulate tumor angiogenesis, metabolic reprogramming, and extracellular matrix remodeling, while also contributing to cancer-associated pain and therapy-induced neurotoxicity. Collectively, this review proposes a hierarchical neuro-tumor interaction framework that provides an integrated conceptual basis for understanding the complexity and context dependency of neural regulation in cancer biology.