Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor with extreme aggressiveness, poor prognosis, and a high mortality rate. To maintain a high rate of proliferation and invasion, GBM cells manipulate many biological processes within the cell and the tumor microenvironment, including intracellular signaling pathways. One of the main signaling pathways with proven roles in GBM pathology is the PI3K/AKT/mTOR signaling pathway, with its molecular alterations considered a hallmark of GBM. Through integrating with various upstream signals from growth factors, nutrients, and energy status, regulatory feedback mechanisms with other signaling pathways, manipulation of glioma stem cells, and epigenetic regulations, this pathway contributes to GBM cell proliferation, growth, angiogenesis, and metastasis, and more importantly escape the effects of available therapies. The extent of involvement of the PI3K/AKT/mTOR signaling pathway grants a more delicate and detailed understanding of this pathway.

This review provides a deep insight into the mTOR pathway in GBM, revealing its modulators and interactions with upstream and downstream regulators. It also provides comprehensive information on the latest mTOR-targeted therapies and resistance mechanisms.