Glioblastoma (GB) is the most common malignant primary brain tumor, with a poor prognosis and limited therapeutic options. The peritumoral brain zone (PBZ) is an area of several centimeters around the tumor that exhibits distinct molecular, radiological, and cellular alterations, promoting GB cell proliferation, invasion, and recurrence. This article explores the biological, clinical, and mechanical features of the PBZ, highlighting its significance in GB progression and treatment challenges. **Cell Spatial Heterogeneity in the PBZ:** - The PBZ shows significant histological differences from the tumor core, characterized by isolated tumor-infiltrating cells and a more invasive phenotype. - GB cells exhibit self-renewal and multi-lineage differentiation properties, with stem-like cells (GSCs) playing a crucial role in tumor initiation, growth, and recurrence. - GSCs in the PBZ are characterized by a mesenchymal-like (MES-like) state, while those in the tumor core are proneural (PN-like) or astrocyte-like (AC-like). **Invasive Strategies of GB Cells:** - GB cells can infiltrate healthy brain parenchyma via white matter tracts and blood vessels, facilitated by tumor angiogenesis and vessel co-option. - Invasive GB cells preferentially move along myelinated fiber tracts and blood vessels, which provide oxygen and nutrients. - White matter invasion is influenced by neuronal activity and calcium-dependent synapse formation, affecting tumor growth and invasion. **Non-Tumor Cells in the PBZ:** - Neurons and astrocytes play a significant role in GB development and survival, influencing GB cell behavior and therapeutic resistance. - Astrocytes co-opt GB cells to maintain proliferation, survival, and migration, while also contributing to the immunosuppressive microenvironment. - Microglia and tumor-associated macrophages (TAMs) exhibit different spatial distributions and functional roles in the tumor core and PBZ, impacting immune response and treatment efficacy. **Tissue Mechanics in the PBZ:** - Physical stress caused by GB growth affects both GB cells and the surrounding PBZ through elevated interstitial fluid pressure (IFP) and solid stress. - IFP and solid stress alter blood vessel integrity, induce hypoxia, and affect immune cell function, hindering drug delivery and treatment response. - Modulating IFP, alleviating solid stress, and manipulating extracellular matrix (ECM) stiffness may enhance treatment outcomes and immune cell access to the tumor. **Clinical Imaging:** - MRI techniques, including T1- and T2-weighted imaging, FLAIR, diffusion-weighted imaging (DWI), and positron emission tomography and computed tomography (PET-CT), are used to detect tumor infiltration and recurrence in the PBZ. - Postoperative peritumoral edema and abnormal signal regions on MRI are associated with poor prognosis and early recurrence. This comprehensive review highlights the complex interactionsGlioblastoma (GB) is the most common malignant primary brain tumor, with a poor prognosis and limited therapeutic options. The peritumoral brain zone (PBZ) is an area of several centimeters around the tumor that exhibits distinct molecular, radiological, and cellular alterations, promoting GB cell proliferation, invasion, and recurrence. This article explores the biological, clinical, and mechanical features of the PBZ, highlighting its significance in GB progression and treatment challenges. **Cell Spatial Heterogeneity in the PBZ:** - The PBZ shows significant histological differences from the tumor core, characterized by isolated tumor-infiltrating cells and a more invasive phenotype. - GB cells exhibit self-renewal and multi-lineage differentiation properties, with stem-like cells (GSCs) playing a crucial role in tumor initiation, growth, and recurrence. - GSCs in the PBZ are characterized by a mesenchymal-like (MES-like) state, while those in the tumor core are proneural (PN-like) or astrocyte-like (AC-like). **Invasive Strategies of GB Cells:** - GB cells can infiltrate healthy brain parenchyma via white matter tracts and blood vessels, facilitated by tumor angiogenesis and vessel co-option. - Invasive GB cells preferentially move along myelinated fiber tracts and blood vessels, which provide oxygen and nutrients. - White matter invasion is influenced by neuronal activity and calcium-dependent synapse formation, affecting tumor growth and invasion. **Non-Tumor Cells in the PBZ:** - Neurons and astrocytes play a significant role in GB development and survival, influencing GB cell behavior and therapeutic resistance. - Astrocytes co-opt GB cells to maintain proliferation, survival, and migration, while also contributing to the immunosuppressive microenvironment. - Microglia and tumor-associated macrophages (TAMs) exhibit different spatial distributions and functional roles in the tumor core and PBZ, impacting immune response and treatment efficacy. **Tissue Mechanics in the PBZ:** - Physical stress caused by GB growth affects both GB cells and the surrounding PBZ through elevated interstitial fluid pressure (IFP) and solid stress. - IFP and solid stress alter blood vessel integrity, induce hypoxia, and affect immune cell function, hindering drug delivery and treatment response. - Modulating IFP, alleviating solid stress, and manipulating extracellular matrix (ECM) stiffness may enhance treatment outcomes and immune cell access to the tumor. **Clinical Imaging:** - MRI techniques, including T1- and T2-weighted imaging, FLAIR, diffusion-weighted imaging (DWI), and positron emission tomography and computed tomography (PET-CT), are used to detect tumor infiltration and recurrence in the PBZ. - Postoperative peritumoral edema and abnormal signal regions on MRI are associated with poor prognosis and early recurrence. This comprehensive review highlights the complex interactions