High semaphorin 4B expression and hypomethylation: Drivers of pancreatic adenocarcinoma progression and immunosuppressive microenvironment

Background: Pancreatic adenocarcinoma has a low incidence but high mortality due to its late-stage diagnosis. Early-stage surgical resection is effective but limited. Semaphorin 4B ( SEMA4B ), a member of the semaphorin family, has an unclear role in pancreatic adenocarcinoma pathogenesis. This study investigated SEMA4B ’s expression, methylation, and its relationship to prognosis and therapy. Materials and Methods: We analyzed SEMA4B using bioinformatics tools including DriverDB v4, UALCAN, Kaplan–Meier Plotter, GSCA, TISIDB, GENI, and DepMap. We examined correlations with copy number variation, promoter methylation, survival, immune cell infiltration, gene pathways, and drug sensitivity. Results: The results show that SEMA4B overexpression positively correlates with copy number variation and is caused by promoter hypomethylation, particularly in early-stage pancreatic adenocarcinoma. Elevated SEMA4B is associated with higher histological grades and poor overall survival. It promotes an immunosuppressive microenvironment by correlating positively with protumor immune cells and negatively with antitumor immune cells. SEMA4B is also associated with abnormal cell cycle pathways and shows sensitivity to several Food and Drug Administration-approved drugs, including Lapatinib and Trametinib. It correlates positively with oncogenes ( KRAS and ERBB2 ) and negatively with tumor suppressors ( SMAD4 ). Conclusions: SEMA4B promoter hypomethylation contributes to its overexpression, with significant diagnostic and prognostic implications. Its role in immunosuppression and as a potential therapeutic target warrants further investigation in preclinical and clinical studies.