Spatial analysis reveals the evolving organization of IDH-mutant glioma

Adult diffuse gliomas comprise malignant cell states interwoven with the non-malignant brain microenvironment. Here, we combine spatial transcriptomics and spatial proteomics of IDH-mutant gliomas to define organizational principles across histological grades. In low-grade tumors, spatial organization is shaped by underlying brain anatomy. We identify a functional white–grey matter junction that restricts cortical invasion and is associated with marked changes in tumor composition and cellular phenotypes. This boundary is preferentially traversed by oligodendrocyte progenitor (OPC)-like malignant cells, suggesting a role in tumor expansion. In contrast, intermediate-grade tumors are largely disorganized, with few recurring interactions between cancer cell states and microenvironmental cell types. In high-grade tumors, hypoxia-associated structure emerges, resembling IDH-wildtype glioblastoma. Together, these findings reveal two independent axes of spatial organization—from anatomy-driven structure in low-grade tumors to hypoxia-driven organization in high-grade tumors—and establish a framework linking tumor grade to recurrent spatial interactions.