Here, we made use of the dichotomy of response and non-response to ICB in a hypermutated glioma model to develop a predictive radiomic imaging signature and to uncover cellular and molecular mechanisms of response and non-response in the glioma immune microenvironment, providing a rationale for targeting programmed death-ligand 1 (PD-L1)-expressing tumor-associated macrophages to overcome resistance to ICB. This evidence concerns the gene CD274 and central nervous system cancer.