SDC2-mediated M2 macrophage polarization via PI3K–Akt signaling predicts poor prognosis and is associated with metastasis in gastric cancer

Background: The management of advanced gastric cancer (GC) remains a major challenge in clinical practice. Searching for reliable prognostic prediction markers and further elucidating the key molecular mechanisms of tumor progression are topics in urgent need of in-depth investigation. Methods: Through applying multiple bioinformatics analyses, we extracted and analyzed datasets from TCGA, GEO, UCSC, TIMER, GEPIA2, TISCH2, and SangerBox to investigate the potential oncogenic mechanisms of Syndecan-2 (SDC2), including the correlation between SDC2 and prognosis, infiltration of immune cells, and the SDC2 expression mapping analysis in GC. Tissue microarray-based immunohistochemical analysis and Western blotting experiments were further applied to validate the oncogenic mechanisms of SDC2 in GC. Results: In the present study, we demonstrated that elevated SDC2 protein levels are a characteristic feature of GC tissues compared to adjacent normal stomach tissues. Clinically, high SDC2 expression was significantly associated with advanced T stage ( P < 0.01), epithelial–mesenchymal transition ( P < 0.01), as well as diffuse and invasive GC subtypes ( P < 0.001). Furthermore, SDC2 expression correlated with poor patient prognosis [hazard ratio (HR) = 3.85, P < 0.001] and was identified as an independent predictor of overall survival in GC patients (HR = 3.073, P < 0.001). Mechanistically, integrated analysis of single-cell transcriptomic data and in vitro experimental validation revealed that SDC2 expression is enriched in M2 macrophages within the tumor immune microenvironment. Knockdown of SDC2 in macrophages significantly suppressed M2 polarization. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses further suggested that the PI3K–Akt signaling pathway may be implicated in SDC2-mediated migration of GC cells Conclusion: Aberrant SDC2 expression serves as an independent predictor of poor survival in GC. Targeting SDC2-mediated immune modulation may offer a promising therapeutic strategy to remodel the tumor microenvironment and improve patient outcomes.