SEMA4C (semaphorin 4C) is a cell surface signaling protein that functions as a ligand for the plexin-B2 receptor (PLXNB2), mediating cell-cell communication critical for development and pathological processes 1. The SEMA4C-PLXNB2 interaction activates downstream signaling cascades including RhoA activation, NF-κB pathway engagement, and AKT phosphorylation 23. In normal physiology, SEMA4C is required for axon guidance and neural cell migration 4. SEMA4C has emerged as a significant oncogenic driver across multiple cancer types. In colorectal carcinoma, osteosarcoma, cervical cancer, hepatocellular carcinoma, and breast cancer, elevated SEMA4C expression promotes epithelial-mesenchymal transition (EMT), a critical process enabling cellular invasion and metastasis 5367. SEMA4C expression correlates with poor prognosis, advanced pathologic stage, and reduced overall survival 5. In breast cancer, SEMA4C promotes tumor cell self-renewal, macrophage recruitment, and angiogenesis through p53 pathway modulation and NF-κB activation 2. In CTC clusters, SEMA4C on tumor cells engages PLXNB2 on monocytes to promote heterotypic clustering, driving metastatic dissemination 1. SEMA4C expression is regulated by microRNAs including miR-31-3p and miR-129-2-3p, offering potential therapeutic targets 67. Additionally, dysregulated SEMA4C signaling associates with diabetic neuropathy development 8.