Single‐Cell Transcriptome Atlas Reveals the Underlying Mechanism of Kynurenic Acid in the Regulation of Tumor Immune Microenvironment in Glioblastoma

Abstract 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.