Simple SummaryDespite years of molecular discoveries and technological advances in surgery, the prognosis of glioblastoma (GBM) still remains unfavorable, with a mean overall survival typically less than 20 months. Recurrence of tumors, and specifically of GBM, could be due to the persistence of a subpopulation of cancer cells with stem cell characteristics. Current investigations have shown the importance of the tumor microenvironment (TME) and its interplay with GBM stem cells through the release of extracellular vesicles. Mechanisms (e.g., M2-macrophages polarization, immunosuppression), factors (cytokines and chemokines), and key players in the TME have a potential role in GBM recurrence, and could be an ideal target for new therapeutic approaches to this highly aggressive tumor. The aim of this short review is to assess the current literature regarding TME, which specifically deals with the interaction between GBM cells and resident tumor-associated macrophages, microglia, lymphocytes, and the implicated role of extracellular vesicles. A better understanding of the interactions between GBM cells, other cells, and factors in the TME can help in investigating the mechanisms underlying chemo- and radioresistance, and in the discovery of new therapeutic approaches to treat and prevent disease progression in GBM patients.AbstractThe invasive nature of glioblastoma is problematic in a radical surgery approach and can be responsible for tumor recurrence. In order to create new therapeutic strategies, it is imperative to have a better understanding of the mechanisms behind tumor growth and invasion. The continuous cross-talk between glioma stem cells (GSCs) and the tumor microenvironment (TME) contributes to disease progression, which renders research in this field difficult and challenging. The main aim of the review was to assess the different possible mechanisms that could explain resistance to treatment promoted by TME and GSCs in glioblastoma, including the role of M2 macrophages, micro RNAs (miRNAs), and long non-coding RNAs (lncRNAs) from exosomes from the TME. A systematic review of the literature on the role of the TME in developing and promoting radioresistance and chemoresistance of GBM was performed according to PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) guidelines. A dedicated literature review search was also performed on the immunotherapeutic agents against the immune TME. We identified 367 papers using the reported keywords. The final qualitative analysis was conducted on 25 studies. A growing amount of evidence in the current literature supports the role of M2 macrophages and non-coding RNAs in promoting the mechanisms of chemo and radioresistance. A better insight into how GBM cells interact with TME is an essential step towards comprehending the mechanisms that give rise to resistance to standard treatment, which can help to pave the way for the development of novel therapeutic strategies for GBM patients.