Nerve-associated niches in gastric cancer progression, metastasis, and immune resistance.
TL;DR
This review synthesizes recent advances linking sensory-neuron circuits, autonomic signaling, perineural inflammation, cancer-induced nerve injury, and systemic neuroendocrine regulation to gastric cancer biology to propose that neural regulation in gastric cancer can be conceptualized across four overlapping niche states.
Abstract
Neural biology is emerging as an important regulatory layer in gastric cancer, extending beyond the conventional pathological concept of perineural invasion. Accumulating evidence indicates that gastric tumors can induce neural remodeling and exploit nerve-associated niches to promote tumor progression, metastatic dissemination, and therapeutic resistance. In this review, we synthesize recent advances linking sensory-neuron circuits, autonomic signaling, perineural inflammation, cancer-induced nerve injury, and systemic neuroendocrine regulation to gastric cancer biology. Particular attention is given to functional neural pathways with translational relevance, including NGF-TRK-mediated nerve expansion, CGRP-RAMP1 sensory-neuron signaling, cholinergic regulation of tumorigenic epithelial programs, and β-adrenergic signaling associated with stress-linked progression and metastasis. We further discuss how nerve-associated niches integrate tumor cells, Schwann cells, cancer-associated fibroblasts, macrophages, innate lymphoid cells, and exhausted T cells to shape immune suppression and response to immune-checkpoint blockade. Single-cell and spatial omics now provide opportunities to define these niches as anatomically and molecularly organized ecosystems rather than isolated neural features. We propose that neural regulation in gastric cancer can be conceptualized across four overlapping niche states: sensory-neuron-high, stromal-neural, adrenergic-high, and PNI-injury-high tumors. This framework may support biomarker-based patient stratification and guide rational therapeutic strategies, including CGRP-RAMP1 blockade, NGF-TRK inhibition, β-blocker repurposing, and neural-targeted combinations with immunotherapy. Future studies should prioritize nerve-centered spatial profiling, functional gastric cancer models, and clinically annotated cohorts to determine whether neural markers can improve prediction of metastasis and treatment response.