TSPAN6-mediated CLEC5A activation drives EMT via the AKT/mTOR pathway and serves as a prognostic biomarker in glioma

Glioma is characterized by diffuse infiltration and therapeutic resistance. Tetraspanin 6 (TSPAN6) is implicated in multiple cancers; however, its role and regulatory mechanism in glioma remain poorly understood. TSPAN6 expression and its clinical relevance were analyzed using data from the TCGA and GEO databases and validated by western blotting. In vitro functions were assessed using CCK‑8, wound healing, and transwell assays. In vivo tumorigenicity was evaluated with an intracranial xenograft model. Co‑immunoprecipitation (Co‑IP) and rescue assays were performed to verify the TSPAN6/CLEC5A/AKT/mTOR axis. Drug sensitivity analysis was also conducted. TSPAN6 was markedly upregulated in glioma tissues and closely associated with high WHO grade, IDH wild‑type, 1p/19q non‑codeletion, and MGMT promoter unmethylation. High TSPAN6 expression predicted poor survival and served as an independent prognostic factor. TSPAN6 knockdown inhibited proliferation, migration, invasion, and EMT in vitro and suppressed intracranial tumor growth in vivo, whereas TSPAN6 overexpression produced opposite effects. Mechanistically, TSPAN6 interacted with CLEC5A and upregulated its expression to promote EMT and activate AKT/mTOR signaling. Rescue assays confirmed that CLEC5A depletion abolished TSPAN6‑mediated oncogenicity. TSPAN6 serves as an effective prognostic biomarker and drives malignant progression of glioma via the CLEC5A/AKT/mTOR axis, representing a promising therapeutic target.