Glioblastoma is one of the deadliest gliomas in clinics with a poor prognosis and 5-years survival rate. One of the most crucial reasons is chemoresistance expressed by multiple glioblastoma cell lines, especially to temozolomide (TMZ), which is the most applied chemotherapy among glioma cases. TMZ-resistance is acquirable along with recurrence of glioblastomas, while the acquiring and expression of TMZ-resistance has largely remained unrevealed. The purpose of this review is to identify and evaluate the roles of two tumor microenvironmental factors, exosomal expression shift, and local hypoxia, acting in the mechanism TMZ-resistance acquiring and expressing in glioblastoma cells. The current related researches indicate that tumor microenvironmental is significantly related to glioblastoma’s TMZ-resistance and tumor growth, while this is prolongedly ignored due to limitation of the experimental methodology and insufficiency on the understanding of glioblastoma intercellular communication mechanisms. Future research is warranted to build up a comprehensive view of microenvironmental factors that influence glioblastoma, which might be beneficial to improve current TMZ therapy and enhance patients’ survival rate in the clinic.
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