A Comprehensive Treatment-Induced Resistance Atlas of Glioblastoma Reveals a Fibrotic Niche Shielding the Tumor from Immunotherapy
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| Format: | Recurso digital |
| Sprache: | Englisch |
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2025
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| _version_ | 1866902248480571392 |
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| author | Wang, Fei |
| author_facet | Wang, Fei |
| contents | <p><span lang="EN-US">Therapeutic 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 299 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.</span></p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_18009414 |
| institution | Zenodo |
| language | eng |
| publishDate | 2025 |
| publisher | Zenodo |
| record_format | zenodo |
| spellingShingle | A Comprehensive Treatment-Induced Resistance Atlas of Glioblastoma Reveals a Fibrotic Niche Shielding the Tumor from Immunotherapy Wang, Fei Glioblastoma spatial niche Immunotherapy Single-Cell Analysis Hypoxia/pathology <p><span lang="EN-US">Therapeutic 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 299 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.</span></p> |
| title | A Comprehensive Treatment-Induced Resistance Atlas of Glioblastoma Reveals a Fibrotic Niche Shielding the Tumor from Immunotherapy |
| topic | Glioblastoma spatial niche Immunotherapy Single-Cell Analysis Hypoxia/pathology |
| url | https://doi.org/10.5281/zenodo.18009414 |