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Purpose of Review: Immunotherapies such as immune checkpoint blockade have revolutionized cancer treatment, but current approaches have failed to improve outcomes in glioblastoma and other brain tumours. T cell dysfunction has emerged as one of the major barriers for the development of central nervous system (CNS)-directed immunotherapy. Here, we explore the unique requirements that T cells must fulfil to ensure immune surveillance in the CNS, and we analyse T cell dysfunction in glioblastoma (GBM) through the prism of CNS-resident immune responses., Recent Findings: Using comprehensive and unbiased techniques such as single-cell RNA sequencing, multiple studies have dissected the transcriptional state of CNS-resident T cells that patrol the homeostatic brain. A similar approach has revealed that in GBM, tumour-infiltrating T cells lack the hallmarks of antigen-driven exhaustion typical of melanoma and other solid tumours, suggesting the need for better presentation of tumour-derived antigens. Consistently, in a mouse model of GBM, increasing lymphatic drainage to the cervical lymph node was sufficient to promote tumour rejection., Summary: For the success of future immunotherapy strategies, further work needs to explore the natural history of dysfunction in GBM tumour-infiltrating T cells, establish whether these originate from CNS-resident T cells and how they can be manipulated therapeutically., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The introduction of immunotherapy with checkpoint receptor blockade has changed the treatment of advanced cancers, at times inducing prolonged remission. Nevertheless, the success rate of the approach is variable across patients and different tumor types, and treatment is often accompanied by severe immune-related side effects, suggesting the importance of co-inhibitory pathway for both prevention of autoimmunity and failure of tumor rejection. A better understanding of how to uncouple anti-tumor activity from loss of self-tolerance is necessary to increase the therapeutic efficacy of checkpoint immunotherapy. In this review, we describe basic concepts of T-cell exhaustion that occur in cancer, highlighting the role of co-inhibitory receptors in contributing to this process while preventing immunopathology. By providing an overview of the current therapeutic success and immune-related burden of secondary effects of checkpoint immunotherapy, we illustrate the "double-edged sword" related to interference with immune-regulatory pathways. Finally, since achieving tumor rejection while preserving self-tolerance is particularly important for the central nervous system, we analyze the case for checkpoint immunotherapy in glioblastoma, the most common adult brain tumor., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)