Advancing precision oncology has driven breakthroughs in understanding oncogenes, tumor suppressors, signaling pathway regulation, apoptosis, and cell cycle control. Molecularly targeted therapies, now integral to malignant tumor treatment, exploit these insights. Functioning as a tumor suppressor, semaphorin 3B (SEMA3B) is frequently inactivated across malignancies via promoter hypermethylation, loss of heterozygosity, and proteolytic cleavage. Its structure‑function relies on receptor complex formation, enabling activation of multiple pathways that induce tumor cell apoptosis, arrest the cell cycle, and competitively inhibit vascular endothelial growth factor‑binding to neuropilin 1. This blockade of the PI3K/Akt pathway suppresses tumor angiogenesis, metastasis, and proliferation. Therefore, comprehensively elucidating SEMA3B and its interactors is crucial for identifying novel biomarkers for early cancer detection and molecular therapeutic targets. Future research should focus on translating these findings into clinical applications, including the development of SEMA3B‑based epigenetic therapies and combination strategies with anti‑angiogenic agents. Key challenges remain in fully delineating the context‑dependent dual roles of SEMA3B, understanding its complex interactions within the tumor microenvironment, and overcoming its inactivation mechanisms for effective therapeutic restoration.
