T cells have long been the center of focus in cancer immunology due to their role in direct killing of cancer cells. Studies that show favorable prognosis associated with higher infiltration of cytotoxic CD8 T cells1 as well as concurrent infiltration of CD8 and CD4 T cells2 have further corroborated the pivotal role T cells play in mediating tumor control or clearance. These findings, coupled with the successful use of therapeutic monoclonal antibodies directed against the programmed cell death 1 (PD-1)–programmed cell death ligand 1 (PD-L1) pathway to reinvigorate effector T cells in checkpoint blockade responsive tumors such as melanoma have shown the importance of studying T-cell activation and exhaustion to fully understand the balance between immune surveillance and tumor growth. Such efforts at using checkpoint blockade to unleash the breaks on T cells have not yielded the same level of success in gliomas, warranting the identification of key players in the tumor microenvironment that might blunt the effects of immunotherapy. In this issue, de Groot and team contribute to our understanding of these tumor-promoting myeloid cells and show us how they might mediate resistance to anti–PD-1 therapy in glioblastoma (GBM) patients.3
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