The fate of malignant glioma (MG) is governed by a multifaceted and dynamic circuit that involves the surrounding cellular and molecular tumor microenvironment. Despite extensive experimental studies, a complete understanding of the complex interactions among the constituents of this microenvironment remains elusive. To clarify this, we introduce a biologically based mathematical model that examines the dynamic modulation of glioma cancer stem cells (GSC) by different immune cell types and intracellular signaling pathways. It simulates the proliferation of glioma stem cells due to macrophage-induced inflammation, particularly involving two microglia phenotypes. The model can be used to regulate therapies by monitoring the GSC self-renewal rates that determine tumor progression. We observe that the GSC population is most sensitive to its own proliferation rate and the relative levels of the activating natural killer (NK) cell stimulatory receptors (NKG2D) versus killer inhibitory receptors (KIR) on NK cells that influence the proliferation or demise of the GSC population. Thus, the two most important factors involved in tumorigenesis or tumor regression are (1) GSC proliferation and (2) the functional status of NK cells. Therefore, strategies aimed at blocking proliferation and enhancing NKG2D and KIR signals should have a potentially beneficial impact for treating malignant gliomas.