Glioblastoma multiforme (GBM) is the most common and aggressive primary human brain tumor. Although comprehensive therapies combining radiotherapy and chemotherapy after surgery can prolong survival, the prognosis is still poor with a median survival of only 14.6 months. Chemoresistance is one of the major causes of relapse as well as poor survival in glioma patients. Therefore, novel strategies to overcome chemoresistance are desperately needed for improved treatment of human GBM. Recent studies have demonstrated that the tumor microenvironment plays a critical role in the chemoresistance of various tumor types, which makes it a suitable target in anti-cancer therapies, as well as a valuable biomarker for prognostic purposes. This review focuses on chemoresistance in GBM induced by stromal cells, including the endothelium of blood vessels, astrocytes, and myeloid cells, as well as non-cellular factors in the tumor microenvironment. Corresponding therapies are discussed, including progressive strategies involving 3-dimensional models integrating engineering as well as biological advances.
