Background <p>Neuroactive ligand–receptor interaction may influence the development of gastric cancer. However, the underlying mechanisms have not been elucidated.</p> Methods <p>Based on single-cell, spatial transcriptome, bulk transcriptome data and immunofluorescence in gastric cancer, we validated cells associated with neuroactive ligand–receptor interaction pathways, prognostic genes and communication signaling direction at spatial level.</p> Results <p>Neuroactive ligand–receptor interaction gene set was closely related to monocyte–macrophages (Mono–Macs), which with high expression of neuroactive ligand–receptor interaction gene set (NEUROhighMono) had significant communication interactions with immune and endothelial cells. Prognostic modeling indicated that patients with high pathway activity had poorer outcomes, characterized by higher stromal scores and elevated immune checkpoint levels. Among related genes, CHRNE was identified as a key marker of poor prognosis, predominantly expressed in Mono–Macs. Integrated spatial transcriptome and immunofluorescence further demonstrated that CHRNE-positive Mono–Macs (CHRNE + Mono) may promote tumor angiogenesis through VEGFA, linking CHRNE to tumor progression and unfavorable prognosis.</p> Conclusions <p>This study explored neuroactive ligand–receptor interactions in gastric cancer, revealing that Mono–Macs were significantly influenced by related genes. CHRNE + Mono may regulate tumor microenvironment by promoting angiogenesis, highlighting CHRNE as a potential driver of tumor progression. These findings suggest that neuroactive ligand–receptor interactions, particularly CHRNE, could offer potential therapeutic strategies for gastric cancer.</p>