KYNU as a Biomarker of Tumor-Associated Macrophages and Correlates with Immunosuppressive Microenvironment and Poor Prognosis in Gastric Cancer.

Background: Kynureninase (KYNU) is a potential prognostic marker for various tumor types. However, no reports on the biological effects and prognostic value of KYNU in gastric cancer (GC) exist.

Methods: GC-associated single-cell RNA sequencing and bulk RNA sequencing (bulk-seq) data were obtained from the Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively. The differential expression of KYNU between GC and normal gastric tissues was first analyzed based on the bulk-seq data, followed by an exploration of the relationship between KYNU and various clinicopathological features. The Kaplan-Meier survival and Cox regression analyses were performed to determine the prognostic value of KYNU. The relationship between KYNU expression and immune cell infiltration and immune checkpoints was also explored. The biological function of KYNU was further examined at the single-cell level, and in vitro experiments were performed to examine the effect of KYNU on GC cell proliferation and invasion.

Results: KYNU expression was significantly elevated in GC samples. Clinical features and survival analysis indicated that high KYNU expression was associated with poor clinical phenotypes and prognosis, whereas Cox analysis showed that KYNU was an independent risk factor for patients with GC. Notably, high expression of KYNU induced a poor immune microenvironment and contributed to the upregulation of immune checkpoints. KYNU-overexpressing macrophages drove GC progression through unique ligand-receptor pairs and transcription factors and were associated with adverse clinical phenotypes in GC. KYNU was overexpressed in GC cells in vitro, and KYNU knockout significantly inhibited GC cell proliferation and invasion.

Conclusion: High KYNU expression promotes an adverse immune microenvironment and low survival rates in GC. KYNU and KYNU-related macrophages may serve as novel molecular targets in the treatment of GC.