By employing cellular (immune cell infiltrate composition, phenotypes, and dynamics), genomic and epigenetic (DNA), transcriptomic (RNA), and proteomic (cytokines) microenvironmental signatures, we dissected the immune-regulatory mechanisms of the GBM microenvironment that evoke resistance to PD-1 inhibition, and showed that co-targeting of PD-1 immune checkpoint and TAM-associated CSF-1R signaling may improve therapeutic efficacy in GBM. Here, CSF1R is linked to glioblastoma.