Integrated Single‐Cell and Spatial Transcriptomics Reveal SERPINE1 as a Key Link Between Macro_SPP1 Macrophages and Stromal Remodeling in Gastric Cancer

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Macrophage heterogeneity is increasingly recognized as an important feature of the gastric cancer tumor microenvironment, yet the macrophage states linked to poor outcome and the molecules connecting them to stromal remodeling remain incompletely defined. Here, we integrated single-cell RNA sequencing data from GSE183904, spatial transcriptomic data from GSE251950, and TCGA-STAD bulk transcriptomic data to characterize macrophage diversity and identify clinically relevant macrophage-associated genes. Cell-cell communication analysis revealed intensified intercellular signaling in tumors, with prominent changes in MIF, COLLAGEN, FN1, LAMININ, and SPP1 pathways. Five macrophage subclusters were resolved. Among them, macro_SPP1 and macro_IL1B signatures were associated with shorter overall survival, whereas macro_C3_CX3CR1 was linked to a more favorable outcome. By integrating macro_SPP1 markers with tumor-associated differentially expressed genes and applying Cox regression together with multiple machine learning approaches, SERPINE1 emerged as the most consistent prognostic candidate. High SERPINE1 expression was associated with poor survival and with stromal, myeloid, and vascular features. Spatial analysis further localized SERPINE1-high regions to microenvironments enriched for fibroblast- and endothelial-related components and for TGF-β, hypoxia, inflammatory, and extracellular matrix remodeling programs. Virtual perturbation suggested that SERPINE1 may influence myeloid and matrix-related transcriptional networks. Functionally, SERPINE1 knockdown reduced proliferation, colony formation, migration, and invasion in gastric cancer cells. Together, these findings identify SERPINE1 as a macro_SPP1-associated molecule with prognostic and functional relevance and suggest a potential link between macrophage-associated programs, stromal remodeling, and malignant behavior in gastric cancer.

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