Construction of a GCSCs-Related Prognostic Risk Model Based on Transcriptomic Data

Gastric Cancer Stem Cells (GCSCs) contribute to tumor progression and treatment resistance, but their heterogeneity and tumor microenvironment interactions remain unclear. We analyzed GSE163558 single-cell RNA-sequencing data from 10 gastric cancer samples and integrated GCSC-related genes with The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA-STAD) training cohort (n = 448) and two independent external validation cohorts, GSE62254 (n = 300) and GSE84437 (n = 483), to construct and validate a six-gene prognostic risk model. Cell–cell communication, metabolic activity, immune infiltration, immunotherapy response, and drug sensitivity were evaluated. Nine cell populations, including a putative GCSC population, were identified. GCSCs showed higher inferred oxidative phosphorylation activity and extensive predicted interactions with tumor-associated cells. The model stratified patients into distinct prognostic groups. High-risk tumors exhibited enrichment of progression-related pathways, including epithelial–mesenchymal transition, and distinct immune features. In PRJEB25780 (n = 78), higher risk scores were associated with immunotherapy non-response, whereas an exploratory analysis of GSE91061 (n = 49) showed a similar trend. The model may support prognostic stratification and provide insights into potential associations with therapeutic response, pending prospective validation.