Chronic Stress Promotes Gastric Cancer Metastasis by Inducing Microbiota‐Associated Kynurenine Accumulation and Macrophage Remodeling

Abstract

ABSTRACT Chronic stress frequently occurs in patients with cancer, yet how stress is translated into pro‐metastatic programs remains unclear. Here, using chronic restraint stress (CRS) in male mice, we show that stress increases metastatic burden and reduces survival in lung metastasis and peritoneal dissemination models, while also increasing overall tumor burden in an orthotopic gastric cancer model. Single‐cell transcriptomics of lung metastases reveals stress‐associated remodeling of tumor‐associated macrophages toward immunosuppressive states, while macrophage depletion attenuates stress‐enhanced metastasis. Stress also reshapes the gut microbiota and enriches Lactobacillus reuteri, and microbiota transfer, antibiotic treatment, co‐housing, and bacterial gavage experiments support a microbiota‐dependent contribution to metastatic progression. Metabolomic analyses identify kynurenine as a stress‐ and L. reuteri‐associated tryptophan metabolite that promotes macrophage‐dependent dissemination, whereas tryptophan deficiency blunts stress‐ and L. reuteri‐enhanced metastasis. Mechanistically, our data support a role for TNFR2–C/EBPβ signaling in Kyn‐induced immunosuppressive macrophage remodeling. In clinical gastric cancer cohorts, higher depressive symptom burden is associated with shorter disease‐free survival, Lactobacillus enrichment, elevated plasma Kyn/Trp ratio, and altered macrophage phenotypes. Together, these findings define a stress–microbiota–tryptophan metabolism–macrophage axis that links chronic stress to gastric cancer metastasis in male mouse models and clinical samples.