Hypoxia-mediated glioblastoma cell-macrophage crosstalk via the TIMP1-LRP1 axis induces immunosuppression.

Glioblastoma is characterized by hypoxia, immune suppression, and poor clinical outcome. Here, we integrated single-cell RNA sequencing, spatial transcriptomics, human glioblastoma specimens, and murine models to define hypoxia-enriched tumor-associated macrophages (hTAMs) and their interaction with hypoxic glioblastoma cells (hGBM cells). hTAMs displayed an immunosuppressive transcriptional program, were enriched in mesenchymal glioblastoma, and were associated with worse survival. Hypoxia increased TIMP1 expression in glioblastoma cells, and tumor-derived TIMP1 engaged LRP1 on macrophages, promoted AKT Ser473 phosphorylation, and shifted macrophage states toward an immunosuppressive phenotype. In orthotopic murine glioma models, tumor-intrinsic Timp1 depletion reduced immunosuppressive macrophage accumulation and prolonged survival. These findings identify a hypoxia-associated tumor-macrophage signaling axis that links glioblastoma adaptation to immune suppression and supports therapeutic targeting of the tumor microenvironment.