Enteric neural-tumor interactions in gastrointestinal malignancies and therapeutic implications

Table 1 Enteric nervous system-mediated local signaling axes shaping the gastrointestinal tumor microenvironment

Source component	Key mediator or molecular cue	Key receptor or binding partner	Target cells	Downstream pathway or mode of action	Biological effect	Ref.
Enteric serotonergic neurons	5-HT	HTR1B/1D/1F	CRC stem cells	Wnt/β-catenin signaling	Promotes CSC self-renewal and enhances tumorigenesis	[49]
Enteric neurons	NPY	Not specified	Intestinal epithelial cells	PI3-K/pAkt/β-catenin and miR-375 suppression	Promote inflammation-induced tumorigenesis	[50]
Enteric glia-associated S100B	S100B	RAGE	colon carcinoma cells	RAGE/p38 MAPK/NF-κB	Promotes a pro-inflammatory, pro-angiogenic, and anti-apoptotic microenvironment	[53]
Cholinergic signal axis	ACh	α7 nicotinic ACh receptor	TAMs	JAK2/STAT3	Reduce CRC cell migration and invasion	[59]
VIP signaling axis	VIP	VPAC/VPAC2	RAW264.7 macrophages	Macrophage repolarization	Increasing the M1/M2 ratio enhances the phagocytosis of tumor cells by macrophages	[60]
Platelets	Serotonin/5-HT	/	Tumor cells	Serotonylation	Inhibits tumor growth, increases functional CD8+ T cell infiltration, and reduces PD-L1	[62]
Cholinergic signaling axis	ACh	M3R	CT-26 murine colon cancer cells	EGFR/AKT/ERK	ACh-M3R signaling supports tumor growth and immunosuppressive/cholinergic/angiogenic markers	[63]
Tumor-associated cholinergic machinery	ACh	M3R	LIM-2405, HT-29 cell	EGFR/ERK	Supports PD-L1/PD-L2 expression, proliferation, and migration; blockade reverses these changes and induces apoptosis	[64]
VIP axis	VIP	/	Hepatic sinusoidal endothelial cells (CRC with liver metastasis)	cAMP/PKA	Inhibits hepatic sinusoidal endothelial cells invasion, migration, and capillary-like structure formation, thereby suppressing intratumoral angiogenesis	[72]
Enteric neurons	Neuronal L1CAM/N-cadherin	/	Colorectal tumor epithelial cells	/	Facilitates adhesion to and migration along enteric neurons, supporting local dissemination/PNI	[75]
Enteric neurons	N-cadherin-dependent adhesion		GC cells	/	Diffuse-type GC cells show stronger adhesion to enteric neurons; N-cadherin blockade reduces adhesion, supporting a potential dissemination/PNI route	[76]

5-HT: 5-hydroxytryptamine; HTR1B/1D/1F: 5-hydroxytryptamine receptor 1B/1D/1F; CRC: Colorectal cancer; CSC: Cancer stem cell; NPY: Neuropeptide Y; TAMs: Tumor-associated macrophages; VIP: Vasoactive intestinal peptide; VPAC: Vasoactive intestinal peptide receptor; VPAC2: Vasoactive intestinal peptide receptor 2; PD-L1: Programmed death-ligand 1; PD-L2: Programmed death-ligand 2; PNI: Perineural invasion; GC: Gastric cancer.