GLS1 Orchestrates Exosome-Mediated Tumor-Endothelial Communication to Facilitate Angiogenesis

Glutaminase 1 (GLS1) drives glutaminolysis to support tumor growth and survival, yet its role in the tumor microenvironment remains poorly understood. Here, we demonstrate that GLS1 promotes angiogenesis in head and neck squamous cell carcinoma (HNSCC) via an exosome-dependent mechanism. In HNSCC xenograft models, genetic silencing of GLS1 or treatment with CB-839 markedly reduces intratumoral angiogenesis. Exosomes from GLS1-deficient cells impair endothelial cell migration and tube formation compared with control exosomes. Proteomic analysis reveals a loss of the pro-angiogenic protein Tenascin C (TNC) in GLS1-deficient exosomes. Mechanistically, loss of GLS1 interferes with USP1-mediated deubiquitination of Caveolin-1 (CAV1), resulting in CAV1 degradation and impaired recruitment of TNC into exosomes. Exosomes deficient in CAV1-TNC complexes subsequently disrupt integrin-dependent FAK-SRC signaling in endothelial cells, inhibiting their angiogenic activity. Collectively, these findings uncover a non-metabolic role of GLS1 in promoting tumor angiogenesis through exosome-mediated CAV1-TNC signaling, suggesting that targeting GLS1 may simultaneously inhibit tumor metabolism and angiogenesis in HNSCC.