Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stemlike cells (GSC) being more sensitive to cytotoxic lymphocytes than glioma differentiated cells (GDC). However, the mechanism behind this higher susceptibility to cytotoxic lymphocytes is unclear. Here we found that the mitochondrial morphology of glioma stemlike cells regulates the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. Moreover, GSC displayed diminished ER-mitochondrial contacts compared to GDC. Forced ER-mitochondrial contacts in GSC increased the cell surface expression of sialylated glycans. Therefore, mitochondrial morphology and dynamism, by modulating ER-mitochondrial interactions, control the surface expression of some glycans and thus play a role in glioma stemlike cell recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma.