High SEMA4B Expression and Hypomethylation: Drivers of Pancreatic Adenocarcinoma (PAAD) Progression and Immunosuppressive Microenvironment.

Background: Pancreatic adenocarcinoma (PAAD) 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 PAAD pathogenesis. This study investigated SEMA4B 's expression, methylation, and its relationship to prognosis and therapy. 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 (CNV), promoter methylation, survival, immune cell infiltration, gene pathways, and drug sensitivity. Results: The results show that SEMA4B overexpression positively correlates with CNV and is caused by promoter hypomethylation, particularly in early-stage PAAD. Elevated SEMA4B is associated with higher histological grades and poor overall survival. It promotes an immunosuppressive microenvironment by correlating positively with pro-tumor immune cells and negatively with anti-tumor immune cells. SEMA4B is also associated with abnormal cell cycle pathways and shows sensitivity to several FDA-approved drugs, including Lapatinib and Trametinib. It correlates positively with oncogenes ( KRAS , ERBB2 ) and negatively with tumor suppressors ( SMAD4 ). Conclusion: 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.