Whole Exome, RNA Sequencing, and snRNAseq of 181 IDH-wildtype Glioblastoma (GBM) tumors (newly diagnosed and recurrent) to identify genomic and transcriptional features associated with anti-PD(L)1 treatment benefit and acquired resistance. Analysis revealed that the mesenchymal (MES) transcriptional subtype is associated with improved overall survival (OS), while treatment with immune checkpoint blockade (ICB) is linked to the outgrowth of non-MES subclones, suggesting an MES-to-non-MES transition as a common resistance mechanism.