Spatial heterogeneity in glioblastoma: Decoding the role of perfusion

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer marked by aggressive growth and therapeutic resistance. A growing body of research highlights substantial spatial heterogeneity within GBM tumors as a critical factor contributing to treatment failure. Advanced molecular techniques, including third-generation genomics, high-resolution metabolomics, and single-cell and spatial transcriptomics, have illuminated the detailed genetic and epigenetic landscape, revealing a complex interplay of molecular modifications. A key determinant of spatial heterogeneity is differential perfusion, which leads to the formation of distinct microenvironmental niches characterized by varying oxygen, nutrient, and growth factor availability. This ITH impacts not only GBM cancer cells but also the entire tumor microenvironment, including immune and other stromal cells. Interactions between cancer cells and the surrounding stroma significantly modulate immune surveillance, frequently promoting tumor malignancy. Perfusion further dictates the plasticity in GBM, enabling their transformation into the aggressive mesenchymal subtype. This review examines how such perfusion-driven differences affect GBM intra-tumoral heterogeneity, focussing on the aspects of immune regulation, and treatment resistance. We discuss emerging therapeutic strategies that target perfusion-induced heterogeneity, including anti-angiogenic and immunotherapeutic approaches. Further, the review emphasizes the importance of the tumor microenvironment and highlights the complex interplay of factors driving GBM progression, paving the way for more effective and personalized treatment strategies aimed at enhancing patient survival.