To investigate the genomic features associated with outcomes to immune checkpoint blockade (ICB) for IDH-wildtype glioblastoma (GBM), we profiled 181 ICB-treated GBM. Baseline tumor transcriptional subtype and associated genetic lesions were predictive of overall survival following ICB. Survival was associated with pre-ICB enrichment for mesenchymal (MES)-like malignant cells, marked by high HLA class I expression, greater infiltration of T cells, and decreased abundance of neural and glial populations. ICB exposure was linked to outgrowth of subclones harboring lesions associated with non-MES subtypes, supporting MES-to-non-MES transition as a common trajectory of acquired resistance to ICB, distinct from treatment with standard chemoradiation.