Glioblastoma (GBM) is an intractable brain cancer that presents a strongly immunosuppressive microenvironment. Alvarado et al. now report that GBM cancer stem cells (CSCs) downregulate Toll-like receptor (TLR) 4 to evade immune suppression, and that activating downstream TLR signaling pathways can reduce tumor growth and disrupt CSC self-renewal.