Integrative single-cell and bulk transcriptomic analysis reveals endoplasmic reticulum stress-related prognostic signatures and tumor microenvironment remodeling in gastric cancer

Gastric cancer remains a major global malignancy, with a particularly high disease burden in East Asia. Its molecular heterogeneity and complex tumor microenvironment contribute to poor prognosis and limited therapeutic efficacy. Although endoplasmic reticulum stress is associated with tumor progression and immune remodeling, its prognostic relevance in gastric cancer remains incompletely characterized. Single-cell and bulk transcriptomic data were integrated to characterize ER stress-related gene-associated cellular states. AUCell was used to quantify single-cell ER stress-related gene activity. A two-stage StepCox[forward] + GBM survival model was constructed in the TCGA-STAD cohort and externally validated in GSE26899. Scissor and CellChat analyses were performed to investigate risk-associated cell populations and intercellular communication. IGFBP7 was selected for exploratory in vitro assessment, with the corresponding experimental data presented in the Supplementary Materials. Ten major cell populations displayed heterogeneous ER stress-related gene activity. The nine-gene model showed prognostic performance in both the training and external validation cohorts. The high-risk group was characterized by enhanced stromal-immune interactions, lower tumor mutation burden, increased immune infiltration and immune checkpoint expression, and distinct predicted drug-response profiles. Exploratory assays showed that IGFBP7 knockdown reduced the viability and invasion of AGS cells. ER stress-related gene-associated molecular patterns were linked to gastric cancer prognosis and tumor microenvironment remodeling. The developed model may provide a framework for prognostic stratification; however, its clinical applicability requires further prospective validation. The exploratory IGFBP7 findings should not be interpreted as establishing a direct mechanistic relationship with ER stress or a diffuse-type gastric cancer-specific effect.