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Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Chronic stress and gut dysbiosis are established risk factors for colorectal adenocarcinoma, yet their synergistic effects on the development of intestinal precancerous lesions remain poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study investigates the molecular mechanisms through which chronic stress interacts with opportunistic pathogen <jats:italic>Listeria monocytogenes<\/jats:italic> to drive intestinal tumorigenesis in <jats:italic>Apc<\/jats:italic><jats:sup>Min\/+<\/jats:sup> mice, with particular focus on the involvement of tumor immune microenvironment remodeling.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The combination of <jats:italic>L. monocytogenes<\/jats:italic> infection and chronic stress, rather than bacterial infection alone, significantly increased colonic adenoma burden and epithelial dysplasia, suggesting that chronic stress establishes a permissive microenvironment for opportunistic pathogens to exert pro-tumorigenic effects. Mechanistically, chronic stress downregulated intestinal epithelial <jats:italic>Muc-2<\/jats:italic> expression and reduced microbial diversity, thereby compromising mucus\/microbial barrier integrity and enhancing <jats:italic>L. monocytogenes<\/jats:italic> colonization. Under dual stress-pathogen exposure, we observed the expansion of myeloid-derived suppressor cells (MDSCs) in spleen and the upregulation of IL-6 in colonic mucosa, which facilitated MDSCs recruitment to tumor sites. Infiltrating MDSCs driven CD8<jats:sup>+<\/jats:sup> T cell depletion through cAMP\/PKA\/CREB signaling, leading to the establishment of immunosuppressive microenvironment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results propose that chronic stress-induced gut barrier disruption may serve as a prerequisite for opportunistic pathogens to accelerate the development of precancerous lesions. Their synergistic effects reshape systemic\/local immune responses, creating a microenvironment conducive to malignant transformation and tumor cell survival. These preliminary findings highlight potential clinical applications of psychological interventions and immune modulation strategies in preventing intestinal carcinogenesis.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1653548","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T04:12:27Z","timestamp":1756872747000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Chronic stress synergizes with Listeria monocytogenes to promote intestinal adenomagenesis via myeloid-derived suppressor 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