Mismatch repair (MMR) deficiency is classically associated with microsatellite instability, a high tumor mutational burden (TMB), and sensitivity to immune checkpoint blockade in cancer. In this issue of the JCI, Puigdelloses Vallcorba et al. reported that this paradigm does not hold true in glioblastoma (GBM). Using genetically engineered mouse models, the authors demonstrated that loss of core MMR genes was insufficient to induce hypermutation or improve survival rates with PD-1 blockade. Instead, mouse models of germline MMR deficiency accelerated malignant progression by promoting the immune milieu toward a myeloid cell-dominant and T cell-suppressed tumor microenvironment. Importantly, the imidazotetrazine agent N3-(2-fluoroethyl) imidazotetrazine (KL-50) bypassed MMR dependence and overcame temozolomide resistance. These findings suggest MMR deficiency in GBM as a driver of immune suppression rather than tumor immunogenicity and carry important implications for therapy selection.