The Gut Microbiota–Tryptophan–Kynurenine Metabolic Axis A Novel Perspective on Remodeling the Immune Microenvironment of Pancreatic Cancer

Keywords: pancreatic cancer; intestinal flora; tryptophan; immune escape

Abstract: ​Pancreatic ductal adenocarcinoma (PDAC) exhibits a five-year survival rate persistently below 10%, as evidenced by recent epidemiological data [1]. Although immune checkpoint inhibitors have demonstrated efficacy in multiple malignancies, their failure in PDAC is attributed to the profoundly immunosuppressive tumor microenvironment (TME). This study elucidates the gut microbiota-tryptophan-kynurenine (Trp-Kyn) metabolic axis as a pivotal regulator of PDAC immune evasion. We demonstrate that microbiota-derived metabolites (e.g., indole-3-propionic acid [IPA] and deoxycholic acid [DCA]) modulate aryl hydrocarbon receptor (AhR) signaling, leading to a 3.2-fold increase in regulatory T cell (Treg) frequency and 42% reduction in effector T cell (Teff) metabolic activity. By integrating multi-omics analyses, we propose a novel "microbiota-Trp-immunity" tri-axial model, which delineates how microbial metabolites orchestrate spatial heterogeneity in the TME. This framework underpins stratified interventions, such as fecal microbiota transplantation (FMT) combined with IDO1 inhibitors, to overcome therapeutic resistance.​

Submission Number: 56