Year: 2026
Type: conference-abstract
Abstract: Background The tumor vasculature actively influences the immune microenvironment and may contribute to immune evasion and resistance to immunotherapy. However, the mechanisms by which vascular niches regulate the function of infiltrating immune cells in glioblastoma remain incompletely understood.Methods We performed single-cell transcriptomic analyses to investigate vascular niche–mediated regulation of immune cells in glioblastoma. Molecular and functional studies were conducted to define signaling pathways and metabolic programs in monocytic myeloid-derived suppressor cells (MDSCs). Genetic ablation and pharmacological inhibition approaches were used to evaluate the role of glutamine synthetase (GS) in tumor immunity and therapeutic responses.Results Single-cell transcriptomic analysis identified a myeloid-selective regulatory mechanism through which the vascular niche promotes immune suppression in glioblastoma. Endothelial cell–derived Wnt5b induced metabolic reprogramming of monocytic MDSCs by activating JNK/ATF2-dependent transcription of GS. MDSCs preferentially utilized GS-mediated glutamine biosynthesis to sustain viability through nucleotide production while simultaneously consuming pro-inflammatory ammonia, thereby reinforcing their immunosuppressive activity within the vascular niche. Genetic deletion of GS in MDSCs reduced tumor-associated immunosuppression and enhanced anti-tumor T-cell responses. Furthermore, pharmacological inhibition of GS increased T-cell infiltration and sensitized glioblastoma to CAR-T cell immunotherapy.Conclusions These findings identify a previously unrecognized vascular–metabolic axis that regulates immune suppression in glioblastoma. Endothelial-derived Wnt5b promotes an immunosuppressive MDSC phenotype through JNK/ATF2-mediated induction of GS and glutamine metabolism. Targeting this vasculature-instructed metabolic checkpoint alleviates immune suppression, enhances T-cell–mediated anti-tumor immunity, and improves responsiveness to CAR-T cell therapy. These results support GS as a promising therapeutic target for overcoming immune resistance and improving cancer immunotherapy outcomes.
Authors: Md Naushad Akhtar, Yi Fan
Institution: University of Pennsylvania
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225335563