Abstract
Despite advances in understanding tumor biology, malignant gliomas remain incurable. While immunotherapy has improved outcomes in other cancer types, comparable efficacy has not yet been demonstrated for primary cancers of the central nervous system (CNS). T cell exhaustion, defined as a progressive decrease in effector function, sustained expression of inhibitory receptors, metabolic dysfunction, and distinct epigenetic and transcriptional alterations, contributes to the failure of immunotherapy in the CNS. Herein, we describe recent advances in understanding the drivers of T cell exhaustion in the glioma microenvironment. We discuss the extrinsic and intrinsic factors that contribute to exhaustion and highlight potential avenues for reversing this phenotype. Our ability to directly target specific immunosuppressive drivers in brain cancers would be a major advance in immunotherapy.