Pericytes in Glioblastoma: Hidden Regulators of Tumor Vasculature and Therapy Resistance

Glioblastoma IDH wild type (GB), the most common malignant primary brain tumor, is characterized by rapid proliferation, extensive infiltration into surrounding brain tissue, and significant resistance to current therapies. Median survival is only 15 months despite extensive clinical efforts. The tumor microenvironment (TME) in GB is highly specialized, supporting the tumor's aggressive behavior and its ability to evade conventional treatments. One critical component is the aberrant vascular network that complicates the delivery of chemotherapy across the blood-brain barrier. Antiangiogenic therapies emerged as a promising option but have shown limited efficacy in extending the survival of these patients. Comprehension of the complex vascular network of GB may be a key to overcoming the limitations of current therapies. Pericytes are gaining recognition within the context of the TME. These mural cells are essential for vascular integrity and may contribute to tumor progression and therapeutic resistance. Although their role has been evidenced in other tumors, they remain underexplored in GB. Pericytes are known to respond to tumor hypoxia and interact with vascular endothelia, influencing responses to DNA damage and antiangiogenic treatments. They actively regulate not only angiogenesis but also the different vasculogenic strategies for tumor neovascularization. Additionally, they affect leukocyte trafficking and tumor-associated macrophages. This review aims to integrate the various functions controlled by pericytes to favor deeper investigation into their actionable potential. Pericytes may represent a promising target for novel therapeutic strategies in order to improve patient outcomes.