Neuron-Associated Transcriptional Enrichment Is Associated with Distinct Biological States and Predicts Poor Prognosis in Gastric Cancer

BACKGROUND: The peripheral nervous system can contribute to tumor development, progression, and metastasis; however, the clinical relevance of neuronal features within the tumor microenvironment in patients with gastric cancer (GC) remains to be fully elucidated. PATIENTS AND METHODS: Bulk transcriptomic and clinical data from publicly available databases were used to evaluate an xCell score that quantified the relative enrichment of neuron-associated gene expression programs in GC tumors. This allowed stratification into neuron score-high and neuron score-low groups within each cohort, with the upper two-thirds defined as high. Associations between neuronal enrichment and tumor biology were evaluated through analyses of neurotransmitter receptor expression, gene set enrichment, tumor microenvironment composition, genomic features, and patient survival. RESULTS: Neuron score-high GC exhibited characteristic enrichment of β-adrenergic, dopamine, and muscarinic acetylcholine receptor gene expression, consistent with enhanced neurochemical signaling potential. At the tumor cell level, the neuron score-high group was associated with activation of epithelial-mesenchymal transition (EMT) programs, whereas cell proliferation-related pathways were preferentially enriched in neuron score-low tumors. Neuron score-high tumors further displayed attenuated antitumor immune infiltration, increased stromal components, and elevated intratumor heterogeneity despite a lower mutation burden. Across both cohorts, neuron score-high tumors were associated with worse overall survival and remained independently associated with prognosis in multivariate analyses. CONCLUSIONS: Neuron score-high GC tumors were consistently associated with distinct patterns of neurotransmitter receptor gene expression, enhanced EMT programs with reduced cell proliferation, attenuated antitumor immune infiltration, increased intratumor heterogeneity, and worse prognosis. These observations identify the neuron score in bulk tumors as a potential indicator of GC biology.