Integrative Omics, Functional Characterization and Androgen Receptor Regulation Reveal the Dual Roles of SEMA5B in Prostate Cancer

This research aimed to study the role of Semaphorin 5B (SEMA5B) in prostate cancer, focusing on its functional characterization, regulation by androgen receptor, and impact on the tumor immune microenvironment. In vitro and in vivo experiments were performed using prostate cancer cell lines and the LNCaP cell line overexpressing SEMA5B was examined using transcriptome sequencing. Immune cell infiltration and metabolic pathways were assessed using bioinformatics tools and functional assays. Despite its association with elevated expression levels in prostate cancer and poorer patient outcomes, SEMA5B demonstrated tumor-suppressive properties in vitro, suppressing cellular proliferation and migration. The androgen receptor was found to transcriptionally upregulate SEMA5B expression. Paradoxically, SEMA5B promoted an immunosuppressive microenvironment by enhancing Tregs and M2 macrophages, potentially explaining its oncogenic association. Metabolic pathway analysis linked SEMA5B to oxidative phosphorylation downregulation. This study uncovers the dual roles of SEMA5B in prostate cancer, highlighting its context-dependent functions as both a tumor suppressor and microenvironment modulator. The AR-SEMA5B axis offers novel therapeutic insights for castration-resistant prostate cancer, emphasizing the need to target immune-metabolic crosstalk in treatment strategies.