Extracellular vesicles (EVs) are released from many tumors including glioblastoma multiforme (GBM), the most common and lethal brain tumor in adults characterized by high resistance to current therapies and poor patient prognosis. Since GSCs are deeply involved in GBM aggressiveness, recent studies have begun to investigate the compounds specifically transported by EVs secreted from these cells, which would be implicated in GBM malignancy. Given the high relevance of the information provided by cancer cell secretome, we performed a proteomic analysis of microvesicles (MVs) and exosomes (EXOs) secreted from GBM-derived stem cells (GSCs). These latter were obtained from surgical specimens of human GBM and expressed P2X7 receptors (P2X7R), which positively correlate with GBM growth and invasiveness.Here, we investigated the proteomic content of GSCs-derived MVs and EXOs following pharmacological stimulation of the ionotropic P2X7R with low affinity to ATP [10], based on the evidence that: i) extracellular ATP levels in glioma cells are in the high micromolar range due to the poor nucleotide metabolism [11]; ii) decreased ATP levels positively correlate with enhanced GBM growth [12]; iii) P2X7R sense high extracellular ATP levels and promote glioma progression [13]; iv) P2X7R are highly expressed in GSCs [14] and their stimulation increases cell aggressiveness by enhancing the expression of epithelial-mesenchymal transition (EMT)-related markers, cell migration/invasion and GSC survival.Our finding indicate that P2X7R stimulation of GSCs caused significant changes in the EV content, mostly ex-novo inducing or upregulating the expression of proteins related to cytoskeleton reorganization, cell motility/spreading, energy supply, protection against oxidative stress, chromatin remodeling and transcriptional regulation. Most of the induced/upregulated proteins has already been identified as GBM diagnostic/prognostic factors, while others have only been reported in peripheral tumors. Our findings indicate that P2X7R stimulation enhances the transport and, therefore, possible intercellular exchange of GBM aggressiveness-increasing proteins by GSC-derived EVs. Thus, P2X7R could be considered as a new druggable target of human GBM, although these data need to be confirmed in larger experimental sets.