Glioma-intrinsic SLC1A3 hijacks the vascular niche to establish an immunosuppressive microenvironment.

Overview

1. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China
2. Institute for Translational Brain Research, Shanghai Medical College, Fudan University, Shanghai, China
3. National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
4. Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai Clinical Medical Center of Neurosurgery, Neurosurgical Institute of Fudan University, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
5. State Key Laboratory of Medical Neurobiology and Ministry of Education (MOE) Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China
6. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States

Abstract

Introduction: Glioblastoma (GBM) is a highly lethal malignancy driven by glioma-initiating cells (GICs). While GICs are known to profoundly remodel tumor microenvironment (TME) to promote progression and immune evasion within the vascular niche, the specific transcriptomic reprogramming and alternative splicing events driving their evolution from neural stem cells (NSCs), and how these intrinsic cellular state changes dictate multi-cellular immunosuppressive networks and checkpoints, remain poorly understood. Unraveling these complex tumor-vascular-immune interactions is critical for identifying novel vulnerabilities and developing effective immunotherapies.

Methods: To decode the GICs’ evolutionary trajectory, we integrated RNA-seq and alternative splicing analysis of NSCs and patient-derived GIC cohorts. The malignant progression was mapped using scRNA-seq pseudotime analysis, and key targets were validated across clinical TCGA cohorts. Furthermore, we employed the large-scale single-cell foundation model, Geneformer, to perform in silico genetic perturbations, integrating it with interactome inference to decipher TME communication. Finally, the proposed tumor-endothelial-T cell multi-cellular axis was functionally validated utilizing in vitro tumor-HUVEC co-culture systems, qPCR, and FACS-based T cell activation (NFAT-Jurkat) assays.

Results: Our multi-omics re-analysis identified extensive alternative splicing and transcriptional reprogramming during GICs evolution, pinpointing SLC1A3 as a core gene significantly upregulated along the malignant pseudotime trajectory and strongly correlated with poor clinical prognosis in GBM. AI-driven in silico virtual knockout utilizing Geneformer revealed that SLC1A3 acts as a master regulator of tumor network stability. Interactome analysis demonstrated that SLC1A3hi tumor cells exhibit intensive communication with endothelial cells via specific ligand-receptor axes (e.g., TNC-ITGB1, PTN-SDC3). In vitro assays confirmed that endothelial cells were educated by SLC1A3hi tumor cells that undergo malignant transition, drastically upregulating immune-suppressive factors, including CD274, TGFB1, IL10, and IDO1. Crucially, tumor-specific knockdown of SLC1A3 dismantled this vascular-immune suppressive niche, significantly restoring T cell activation in a multicellular co-culture model.

Discussion: Our findings establish SLC1A3 not merely as an intrinsic driver of glioma development, but as a critical upstream node orchestrating a cascading tumor-endothelial-T cell immunosuppressive axis. By leveraging AI-based foundation models alongside robust biological validation, we uncovered a novel mechanism of vascular-mediated immune evasion, highlighting SLC1A3 as a highly promising therapeutic target to reprogram the glioblastoma microenvironment and restore anti-tumor immunity.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE242328, at NCBI GEO; found in the text, “Transcriptome signatures reveal unique…”

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 29 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 12 authors, 8 keywords, 9 MeSH terms, 64 references.

Cite

This paper

Lin, H., Liu, C., Chen, X., Zhao, Y., Lyu, Y., Zhang, B., Song, H., Fan, X., Li, S., He, Z., Yang, H., & Mao, Y. (2026). Glioma-intrinsic SLC1A3 hijacks the vascular niche to establish an immunosuppressive microenvironment. Frontiers in immunology, 17, 1824726. https://doi.org/10.3389/fimmu.2026.1824726

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