The SSH phosphatase family as a potential driver of immune microenvironment remodeling and therapeutic response in gastric cancer: a multi-omics analysis

The Slingshot (SSH) phosphatase gene family—comprising SSH1, SSH2, and SSH3—governs actin dynamics via cofilin activation. Although SSHs dysregulation has been documented in several malignancies, its collective impact on gastric cancer (GC) pathogenesis remains unexplored. Transcriptomic and single-cell data of GC patients were retrieved from TCGA and GEO cohorts. cBioPortal, GeneMANIA, TISIDB, and MCP‑counter were used to delineate mutation frequencies, protein-protein interactions, and immune cell infiltration patterns. Drug sensitivity was assessed using the oncoPredict algorithm against the GDSC database. In vitro silencing of SSH1 was performed to validate its oncogenic role in GC cells. SSH1/2/3 mRNA expression was significantly elevated in GC, and high expression correlated with shorter survival. All three SSHs showed strong positive associations with immune cell infiltration, particularly neutrophils, and with multiple immune checkpoint regulators, suggesting a potential role in remodeling the GC immune microenvironment. Transcriptomic analyses uncovered a correlation between SSH family and cancer stem cell (CSC) ‑related transcriptional signatures, which warrants further functional validation. Drug sensitivity analysis revealed that SSH expression correlated with IC50 values of several chemotherapeutic agents. Knockdown of SSH1 suppressed GC cell proliferation and colony formation. The SSH family acts as a pro‑oncogenic module in GC and may contribute to tumor progression through immune microenvironment remodeling and modulation of therapeutic responsiveness. SSHs may serve as potential biomarkers and candidate targets for future combination therapeutic strategies in GC.