表征治疗诱导性与遗传性错配修复缺陷型超突变胶质瘤的空间肿瘤微环境

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.