Local Tumor Microenvironment Niches Correlate With Survival And Immunotherapy Response In Human Glioblastoma

2026 · doi:10.64898/2026.02.23.707276
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This study identified specific niches within the human glioblastoma tumor microenvironment that correlate with patient survival and response to immunotherapy.

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This study analyzed spatial and single-cell transcriptomic data integrated with histology from 25 glioblastoma (GBM) tumors to characterize tumor microenvironment (TME) heterogeneity, estimating immune and other cell compositions across more than 46,000 spatial spots. The authors identified spatial associations between mesenchymal-like cancer cells and monocyte-derived macrophages and clustered spots into six TME niche classes with distinct pathway activation patterns. They then used spatial-transcriptomics-informed deconvolution of bulk RNA-seq to show that niche composition correlated with patient survival, where a mesenchymal-like, monocyte-derived macrophages-rich, hypoxic niche was associated with lower survival and a microglia-derived macrophages-enriched niche with longer survival; in immunotherapy-treated patients, specific niches correlated with response to PD-1 inhibitors. The paper’s limitation is that niche categorization and correlations are derived from retrospective integrations across existing datasets rather than a single prospective clinical study. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Background Glioblastoma (GBM) is an aggressive form of primary brain cancer. Recent efforts to characterize GBM using single-cell or spatially-resolved transcriptomics have revealed a tremendous intra-tumoral heterogeneity between malignant cells and between different tumor areas. However, most efforts have focused on malignant cells, and the spatial and cellular heterogeneity of the tumor microenvironment (TME) remains poorly understood. Moreover, it is unclear how TME compositions and organizations influence clinical outcomes for patients. Results Integrating spatial transcriptomics, single-cell RNA-seq and histology on 25 tumors, cellular composition of the TME was estimated on over 46,000 55-μm wide spots. Spatial associations were revealed between mesenchymal-like cancer cells and monocyte-derived macrophages. Spots were clustered into six unique classes of TME, exhibiting differential composition of malignant and immune cells, and distinct activation of biological pathways. Spatial transcriptomics-informed deconvolution of large-scale bulk RNA-seq datasets revealed that the niche composition of tumors associated significantly with patient survival and response to immunotherapy. Mesenchymal-like, monocyte-derived macrophages-rich and hypoxic niche N1 associated with lower overall survival while oligodendrogial progenitor-like and microglia-derived macrophages-enriched niche N5 is associated with longer patients’ survival. Analysis of data from patients treated with immunotherapy showed that niches N1 and mixed mesenchymal-like and astrocyte-like niche N3 associated with response to PD-1 inhibitors. Conclusions Our results show that GBM exhibits a strong spatial heterogeneity of TMEs, with distinct categories of niche. The niche composition of tumors associated with survival and immunotherapy response. Our results suggest incorporation of TME niches as biomarkers for risk stratification and therapeutic decisions for patients.
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Abstract

Background Glioblastoma (GBM) is an aggressive form of primary brain cancer. Recent efforts to characterize GBM using single-cell or spatially-resolved transcriptomics have revealed a tremendous intra-tumoral heterogeneity between malignant cells and between different tumor areas. However, most efforts have focused on malignant cells, and the spatial and cellular heterogeneity of the tumor microenvironment (TME) remains poorly understood. Moreover, it is unclear how TME compositions and organizations influence clinical outcomes for patients.

Results

Integrating spatial transcriptomics, single-cell RNA-seq and histology on 25 tumors, cellular composition of the TME was estimated on over 46,000 55-μm wide spots. Spatial associations were revealed between mesenchymal-like cancer cells and monocyte-derived macrophages. Spots were clustered into six unique classes of TME, exhibiting differential composition of malignant and immune cells, and distinct activation of biological pathways. Spatial transcriptomics-informed deconvolution of large-scale bulk RNA-seq datasets revealed that the niche composition of tumors associated significantly with patient survival and response to immunotherapy. Mesenchymal-like, monocyte-derived macrophages-rich and hypoxic niche N1 associated with lower overall survival while oligodendrogial progenitor-like and microglia-derived macrophages-enriched niche N5 is associated with longer patients’ survival. Analysis of data from patients treated with immunotherapy showed that niches N1 and mixed mesenchymal-like and astrocyte-like niche N3 associated with response to PD-1 inhibitors.

Conclusions

Our results show that GBM exhibits a strong spatial heterogeneity of TMEs, with distinct categories of niche. The niche composition of tumors associated with survival and immunotherapy response. Our results suggest incorporation of TME niches as biomarkers for risk stratification and therapeutic decisions for patients. Competing Interest Statement FP is a consultant for Immunocore and SOTIO Biotech. SMP is co-founder and holds shares in Trogenix Ltd., a University of Edinburgh spin-out company that is exploring novel viral immunotherapies for GBM and other solid cancers. All other authors declare that they have no competing interests. Footnotes ↵† Deceased 1st May 2023

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