GLUL Confers Perivascular Cancer‐Associated Fibroblasts With Pro‐Angiogenic Capacity to Promote Glioma Progression

Abstract Glioblastoma (GBM) is a malignant brain tumor characterized by profound angiogenic activity and immunosuppressive features. A burgeoning body of research has focused on elucidating the functional effects of stromal cells within the tumor microenvironment (TME) and developing stroma‐targeted therapeutic strategies. Notably, cancer‐associated fibroblasts (CAFs), essential stromal components of the TME, have garnered significant attention for their functional orchestration in glioma progression. The proteomic landscape of human primary CAFs from GBM samples has revealed the dynamic remodeling of differential protein expression in the TME, but the functional role of glutamate‐ammonia ligase (GLUL) as a novel CAF target remains elusive. This study confirms that GLUL knockdown profoundly abrogated the architectural intricacy inherent to CAF‐supported vasculature in vitro and in vivo. Additionally, CAF‐specific GLUL knockdown attenuates tumor growth and extends median survival in a humanized orthotopic glioma model. Furthermore, GLUL‐driven activation of PI3K/AKT signaling as the central regulator of CAF‐mediated vascular niche formation is delineated in glioma progression. This study highlights that targeting GLUL in CAFs is a novel stroma‐focused therapeutic paradigm for GBM by disrupting pro‐angiogenic signaling. Collectively, these findings elucidate key aspects of CAF biology and their regulatory functions in tumor progression, underscoring the therapeutic potential of targeting CAFs in GBM.