Enteric neuro-immune-tumor ecosystem in pancreatic, colorectal, and gastric malignancies: context dependence and translational priorities

Pancreatic ductal adenocarcinoma, colorectal cancer, and gastric cancer arise in densely innervated tissues, yet neural regulation remains incompletely integrated into tumor immunology. This narrative review uses the term “enteric neuro-immune-tumor ecosystem” for an operational framework comprising five anatomy-anchored evidence domains: local enteric nervous system remodeling, extrinsic autonomic and sensory regulation, perineural invasion-associated niches, glial-cell-mediated signaling, and microbiota-neuro-immune communication. Hepatocellular carcinoma and cholangiocarcinoma are treated as a labeled hepatobiliary extension. Evidence is described consistently as GI-direct evidence, GI-physiology evidence, or cross-tumor evidence and is interpreted separately from study maturity and translational status. Available studies indicate context-dependent associations or effects of sympathetic, parasympathetic, sensory, and glial signals on CD8+ T-cell function, myeloid-cell states, stromal organization, and cancer-cell state; the direction and magnitude vary with tumor type, disease stage, anatomical site, neural subtype, and receptor-bearing cell. Cancer-induced nerve injury is associated with IL-6- and type I interferon-related inflammation and dysfunctional antitumor immunity, whereas selected cholinergic and sympathetic circuits can restrain tumor growth in specific preclinical models. Candidate interventions, including β-adrenergic blockade, NGF/Trk inhibition, denervation, and neurotoxin-based approaches, are supported mainly by preclinical studies or retrospective associations. Prospective tumor-specific evidence and validated selection biomarkers remain limited, and none of these interventions has an approved oncologic indication for neuro-immune modulation. A context- and evidence-matched approach may help define when neural targeting merits clinical testing and when it could disrupt protective neural functions.