A Comprehensive Treatment-Induced Resistance Atlas of Glioblastoma Reveals a Fibrotic Niche Shielding the Tumor from Immunotherapy

2Therapeutic resistance in IDH-wildtype glioblastoma (GBM) is driven by profound cellular plasticity and a structured immunosuppressive tumor microenvironment (TME). Here, we present the Glioblastoma Resistance Insights from Treatment Atlas (GRIT-Atlas), the most comprehensive single-cell resource to date, encompassing nearly one million cells from 296 samples across primary and recurrent cohorts, including those treated with immune checkpoint blockade (ICB) and anti-angiogenic combination therapy. We identify a convergent evolutionary trajectory where therapeutic pressure selects for a specific malignant state, cNMF7 (MES-like), characterized by a synergy of hypoxia, stemness, and inflammatory signaling. Integrating spatial transcriptomics across 48 patient sections, we define a "Spatial Resistance Triad"--a core functional unit composed of cNMF7 cells, differentiation-arrested E-MDSCs, and Type VI Collagen-secreting myCAFs. This triad specifically colonizes the hypoxic microvascular proliferation (MVP) and pseudopalisading necrosis (PAN) niches. Mechanistically, we show that myCAFs act as stromal architects, constructing a fibrotic scaffold through a Collagen/Fibronectin-CD44 signaling axis. This spatial infrastructure not only physically excludes cytotoxic T cells but also provides essential cues to sustain malignant plasticity and myeloid-mediated immunosuppression. Our findings across seven independent cohorts and pan-cancer validation underscore the clinical significance of this axis in driving immunotherapy failure. Collectively, the GRIT-Atlas provides a blueprint for dismantling the "immunosuppressive sanctuaries" of GBM to overcome therapeutic resistance.