Hijacking migration: CXCL12-functionalized hydrogels as a new frontier in glioblastoma therapy

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. It is known for extensive infiltration, significant variability, and a high recurrence rate. Current standard treatments include maximal surgical removal and chemoradiotherapy. However, they offer limited benefit because of the tumor's invasive nature and resistance to systemic therapies. The blood-brain barrier (BBB) also impedes the delivery of effective treatments, underscoring the urgent need for innovative therapeutic approaches and delivery systems that can bypass the BBB and target disseminated tumor cells. The chemokine CXCL12, which interacts with the CXCR4 receptor, plays an important role in GBM progression by regulating key processes, including cell migration, invasion, blood vessel formation, maintenance of glioma stem-like cells, and the immune response. The CXCL12/CXCR4 signaling pathway creates chemotactic gradients that drive GBM cell movement into healthy brain tissue. This contributes to tumor recurrence and therapy resistance. Targeting this pathway could lead to a more effective strategy for directing tumor cells toward treatment areas. Accordingly, researchers have developed CXCL12-functionalized hydrogels as new therapeutic platforms. These hydrogels can capture invasive GBM cells and provide localized, sustained-release treatments across the BBB. This review explains the role of the CXCL12/CXCR4 axis in GBM biology and offers a thorough overview of hydrogel-based delivery systems, focusing on chemotactic mechanisms and CXCL12-functionalized hydrogels. It also discusses ongoing challenges and outlines future steps for applying these systems in clinical settings.