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.