Enteric neural-tumor interactions in gastrointestinal malignancies and therapeutic implications

The enteric nervous system (ENS), long recognized for coordinating myenteric-submucosal motility, secretion, barrier function, and intrinsic afferent signaling and chemical coding, has emerged as a participant in gastrointestinal cancer biology. This review synthesizes evidence positioning the ENS as a mechanistic bridge linking tumor microenvironment (TME) dynamics with systemic brain-gut axis regulation in gastrointestinal cancers. Locally, tumors remodel enteric neuroglial networks through neurotrophic and inflammatory cues, promoting axonogenesis, perineural invasion, galanin-related gastric myenteric remodeling, and phenotypic shifts in enteric glia. Conversely, ENS-derived neurotransmitters and glial mediators, including acetylcholine, serotonin, vasoactive intestinal peptide (VIP)/VIP receptor 2 (VIPR2), substance P, nitric oxide, prostaglandin E2, and S100B, influence cancer stemness, proliferation, VIP/VIPR2-mediated ILC3 and macrophage polarization, immune evasion, metabolic adaptation, and stromal remodeling. Systemically, the gut-brain axis relays stress, PER2-related circadian disruption in APC-driven tumorigenesis, and autonomic outflow to modulate tumor progression via ENS-integrated circuits. This bidirectional crosstalk establishes a “neuro-epithelial-immune niche” within the TME. Recognition of this niche has therapeutic implications, as targeting enteric neurotransmitter receptors, neurotrophin signaling, glial mediators, denervation-related and stress-neural axes has shown preclinical efficacy and repurposing potential. Integrating enteric neuroscience into gastrointestinal oncology reframes tumors as ecosystems shaped by malignant cells, stroma, and gut-wall neural circuits, improving outcomes.