Abstract: Glioblastoma is the most common and aggressive primary brain tumor, and patients with glioblastoma have a median overall survival of 12-16 months after standard therapy. The main complexity of glioblastoma therapy is tumor heterogeneity. Recent advances in single-cell and cell biology research indicate that the combination and cross-transition of transcriptome subtypes are related to therapeutic effects on glioblastoma. Thus, this study aimed to review the molecular mechanism and environmental factors related to the formation and transition of malignant glioblastoma subtypes (mesenchymal subtype) with respect to subtype distribution in the tumor microenvironment and integrate the mechanism into the clinical problem to discuss future glioblastoma therapeutic strategies.