Significance: Gliomas exhibit high proportions of glioma stem cells (GSCs), anoikis resistance, increased brain parenchyma invasion, and resistance to therapy with high recurrence. GSCs display protective autophagy, a self-mediated lysosomal degradation process that balances sources of energy at critical times of stress. Protective autophagy in GSCs promotes resistance to anoikis, programmed death resulting from growth in an anchorage-independent manner. MDA-9 is critical in maintaining protective autophagy in GSCs, thereby contributing to anoikis-resistance. MDA-9 regulates critical molecules, including BCL2 and EGFR, which control autophagy. A link between MDA-9 and protective autophagy and anoikis-resistance identifies an Achilles’ heel of glioblastoma multiforme that may be exploited to define enhanced therapies with improved prognosis and decreased recurrence. Accordingly, targeting MDA-9 may represent a viable therapeutic strategy for glioblastoma multiforme.

Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell–derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.