Cancer-associated enteric glial cell abundance as a prognostic marker in gastric cancer revealed by single-cell analysis

Enteric glial cells (EGCs), essential regulators of gastrointestinal barrier function, immune responses, and neuro-epithelial homeostasis, remain largely unexplored in the context of gastric cancer (GC). EGCs are a specialized population of peripheral neuroglia that, along with enteric neurons, make up the enteric nervous system. While neural innervation in GC has been increasingly recognized, the presence and functional significance of cancer-associated EGCs (CAEGCs) within the gastric tumor microenvironment (TME) remain undefined. In this study, we utilized integrative single-cell transcriptomic analysis of human GC to identify a rare but distinct population of CAEGCs residing within the stromal compartment. Defined by consistent expression of canonical glial markers, this CAEGC population emerged as a robust and reproducible signature across six independent datasets. To evaluate clinical relevance, we then applied LASSO-Cox regression modeling to The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) cohort to establish a GAEGC-derived glial signature that stratified GC patients into high- and low-risk groups with significant survival differences (p < 0.001) and distinct molecular features. This GAEGC-derived glial signature also aligned with established molecular subtypes and predicted response to therapy. Our findings reveal a prognostically relevant and previously underappreciated population of CAEGC-like stromal cells within the GC TME. This GAEGC-derived glial signature offers a way to predict GC relapse risk and survival, and it highlights neuro-glial interactions as a potential site of therapeutic intervention in GC.