Single‐Cell Transcriptome Atlas Reveals the Underlying Mechanism of Kynurenic Acid in the Regulation of Tumor Immune Microenvironment in Glioblastoma
Tryptophan metabolism plays a critical role in glioblastoma (GBM), however, the regulatory functions of kynurenic acid (KYNA) in this context remain poorly understood. Using an in-house clinical cohort, targeted metabolomic analysis revealed significantly downregulated KYNA levels in GBM tissues compared to non-tumor brain tissues. Further investigation demonstrated that KYNA administration markedly reduced tumor burden in an orthotopic GBM mouse model. Through integrated cytometry by time-of-fight (CyTOF), single-cell RNA sequencing (scRNA-seq), proteome, and flow cytometry analyses, this study delineated the alterative tumor immune landscape following KYNA treatment. Specifically, KYNA remodeled the immunosuppressive myeloid compartment within the GBM microenvironment. Additionally, KYNA reversed T cell exhaustion signatures, enhanced cytotoxic function, thereby augmented anti-tumor T cell responses. Notably, the anti-tumor effects of KYNA are abrogated in T cell-deficient mouse models (nude and Rag2-/-), confirming its dependence on adaptive immunity. In summary, this study highlights the therapeutic potential of KYNA in GBM and provides a comprehensive, multi-omics-based understanding of its immunomodulatory mechanisms.
Authors
- Guangyi Jiang
- Jiajun Chen (ORCID: https://orcid.org/0009-0009-3837-9400)
- Guohua Zhao (ORCID: https://orcid.org/0000-0003-0593-9175)
- Dongming Yan (ORCID: https://orcid.org/0000-0001-6036-2298)
- Di Chen (ORCID: https://orcid.org/0000-0001-5644-5736)
- Ruokun Chen
- Liming Sun (ORCID: https://orcid.org/0000-0002-0136-5605)
- Hongjiang Li (ORCID: https://orcid.org/0000-0001-5039-9660)
- Hongwei Li (ORCID: https://orcid.org/0000-0002-5328-6407)
- Zi Ye (ORCID: https://orcid.org/0000-0001-5393-5959)
- Yong Zhang (ORCID: https://orcid.org/0000-0002-1303-0458)
- Jing Yan (ORCID: https://orcid.org/0000-0001-6245-7434)
- Rong Zeng (ORCID: https://orcid.org/0009-0006-1183-5304)
- Yake Xue
- Xueyuan Li (ORCID: https://orcid.org/0000-0002-0138-2296)
- Hongwei Zheng (ORCID: https://orcid.org/0000-0001-5366-5936)
- Yuchen Ji (ORCID: https://orcid.org/0000-0002-4828-5338)
- Qinghao Zhang (ORCID: https://orcid.org/0000-0002-5744-9859)
- Lixin Wu (ORCID: https://orcid.org/0009-0005-8931-0578)
- Xuqiang Zhu
Institutions
- ShanghaiTech University (CN)
- First Affiliated Hospital of Zhengzhou University (CN)
- Shanghai Clinical Research Center (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-12
- DOI
- https://doi.org/10.1002/advs.202507705
- Primary Topic
- Tryptophan and brain disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- China Postdoctoral Science Foundation
- Natural Science Foundation of Henan Province
- Henan Medical Science and Technique Foundation