Abstract 7429: Characterizing the spatial tumor microenvironments of therapy-induced and hereditary mismatch-repair-deficient hypermutated gliomas

Abstract Hypermutation in gliomas is observed in some recurrent tumors and hereditary cancer syndromes; however, the extent to which elevated tumor mutational burden influences the tumor microenvironment and contributes to a more aggressive clinical phenotype remains unclear. We comprehensively define the spatial tumor microenvironments in 49 glioma tissues from 32 patients by mapping the transcriptional and spatial organization of 2.3 million single cells in situ. Longitudinal analyses reveal an enrichment of proliferating, stem-cell-like malignant states in both therapy-induced and hereditary mismatch-repair (MMR)-deficient hypermutated tumors, consistent with the increased proliferative activity observed with hypermutation. Additionally, despite a shared MMR-deficiency, malignant cells from chemotherapy-induced and hereditary origin hypermutated tumors exhibit distinct transcriptional programs, underscoring the influence of mutation etiology on malignant cell states. Hypermutation at recurrence does not consistently correlate with increased lymphocytic infiltration or response to immune checkpoint blockade, despite clear transcriptional changes. Together, our single-cell spatial maps illustrate how hypermutation of distinct origins drives divergent cellular transcriptional programs and tissue architecture in gliomas, highlighting the role of tumor-immune microenvironment in shaping cancer evolution and informing therapeutic strategies. Citation Format: Chae Yun (Kate) Cho, Bo Zhao, Lingqun Ye, Inés Martín-Barrio, Yonathan Lissanu, Kadir C. Akdemir. Characterizing the spatial tumor microenvironments of therapy-induced and hereditary mismatch-repair-deficient hypermutated gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7429.