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Peer-reviewedCC BYFrontiers in Cell and Developmental Biology

Defining glioma ecosystem states with AI-driven single-cell and spatial multi-omics: immune-niche reprogramming and therapeutic vulnerabilities

  • Zhizhen Qin1
  • Zhizhen Qin2
  • Yibo Zhang1
  • Bo Wen3
  • Jiaxin Li1
  • Zhenzhen Chen4
  • Xin Li1
  • Xin Li2
  • Dongsheng Kong1
4 affiliations
  1. 1Senior Department of Neurosurgery, The First Medical Center of PLA General Hospital, Beijing, China
  2. 2Department of Neurosurgery, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
  3. 3School of Science and Technology, Hong Kong Metropolitan University, Kowloon, China
  4. 4Department of Critical Care Medicine, The Third Medical Center of Chinese PLA General Hospital, Beijing, China
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Abstract

ObjectiveTo define clinically relevant glioma ecosystem states (recurrent spatial configurations of malignant programs and microenvironmental niches) and identify immune-niche-dependent therapeutic vulnerabilities using single-nucleus, spatial, tissue, and machine-learning analyses.MethodsPublic multi-omics datasets were integrated with institutional single-nucleus RNA sequencing from 12 tumors, spatial transcriptomics from 6 IDH-wildtype glioblastomas, multiplex immunofluorescence in 138 FFPE cases, and glioma–macrophage co-culture assays.ResultsThree ecosystem states were identified. The hypoxic myeloid-mesenchymal state showed the highest MES-like, hypoxia, SPP1/APOE myeloid, and temozolomide-resistance scores, the lowest CD8+ T-cell density, and the shortest tumor–myeloid distance. In 96 IDH-wildtype glioblastomas, this state independently predicted shorter progression-free survival (HR 2.19, 95% CI 1.22–3.92) and overall survival (HR 2.07, 95% CI 1.12–3.81) after adjustment for major clinical and molecular covariates. Defactinib plus temozolomide reduced viability, colony formation, and migration by 56.0%, 61.3%, and 57.8%, respectively, under macrophage-conditioned culture.ConclusionSpatially organized tumor–immune ecosystems provide prognostic information and highlight potentially actionable SPP1–CD44/FAK–SRC signaling in glioblastoma as a candidate target for individualized therapeutic stratification approaches.

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Cite

BibTeXRIS
BibTeX
@article{qin2026defining,
  title = {{Defining glioma ecosystem states with AI-driven single-cell and spatial multi-omics: immune-niche reprogramming and therapeutic vulnerabilities}},
  author = {Zhizhen Qin and Zhizhen Qin and Yibo Zhang and Bo Wen and Jiaxin Li and Zhenzhen Chen and Xin Li and Xin Li and Dongsheng Kong},
  journal = {Frontiers in Cell and Developmental Biology},
  year = {2026},
  month = oct,
  doi = {10.3389/fcell.2026.1943227},
  url = {https://doi.org/10.3389/fcell.2026.1943227},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Defining glioma ecosystem states with AI-driven single-cell and spatial multi-omics: immune-niche reprogramming and therapeutic vulnerabilities
AU  - Zhizhen Qin
AU  - Zhizhen Qin
AU  - Yibo Zhang
AU  - Bo Wen
AU  - Jiaxin Li
AU  - Zhenzhen Chen
AU  - Xin Li
AU  - Xin Li
AU  - Dongsheng Kong
PY  - 2026
DA  - 2026/10/23
JO  - Frontiers in Cell and Developmental Biology
DO  - 10.3389/fcell.2026.1943227
UR  - https://doi.org/10.3389/fcell.2026.1943227
AB  - ObjectiveTo define clinically relevant glioma ecosystem states (recurrent spatial configurations of malignant programs and microenvironmental niches) and identify immune-niche-dependent therapeutic vulnerabilities using single-nucleus, spatial, tissue, and machine-learning analyses.MethodsPublic multi-omics datasets were integrated with institutional single-nucleus RNA sequencing from 12 tumors, spatial transcriptomics from 6 IDH-wildtype glioblastomas, multiplex immunofluorescence in 138 FFPE cases, and glioma–macrophage co-culture assays.ResultsThree ecosystem states were identified. The hypoxic myeloid-mesenchymal state showed the highest MES-like, hypoxia, SPP1/APOE myeloid, and temozolomide-resistance scores, the lowest CD8+ T-cell density, and the shortest tumor–myeloid distance. In 96 IDH-wildtype glioblastomas, this state independently predicted shorter progression-free survival (HR 2.19, 95% CI 1.22–3.92) and overall survival (HR 2.07, 95% CI 1.12–3.81) after adjustment for major clinical and molecular covariates. Defactinib plus temozolomide reduced viability, colony formation, and migration by 56.0%, 61.3%, and 57.8%, respectively, under macrophage-conditioned culture.ConclusionSpatially organized tumor–immune ecosystems provide prognostic information and highlight potentially actionable SPP1–CD44/FAK–SRC signaling in glioblastoma as a candidate target for individualized therapeutic stratification approaches.
SN  - 2296-634X
ER  -