Gut Bacterium Morganella morganii-Secreted Proteins Promote Colorectal Tumor Progression through CD137 Upregulation via NF-κB Activation.

BACKGROUND: The development and progression of Colorectal Cancer (CRC) are closely linked to gut microbiota dysbiosis. However, the pathogenic functions and mechanisms of specific microbiota-derived factors in CRC are not well defined. In this study, we focused on Morganella morganii (M. morganii), a commensal bacterium significantly enriched in the gut of CRC patients, to investigate its potential role in promoting CRC progression. METHODS: We first compared the fecal abundance of M. morganii between patients with CRC and healthy controls in a clinical cohort. From its culture supernatant, a high-molecularweight secreted protein mixture, designated M-T3, was purified. In vitro, HCT116 human CRC cells were treated with M-T3 to assess its effects on proliferation, clonogenic potential, and migration. The role of the NF-κB pathway was examined using pharmacological inhibition. In vivo, an HCT116 xenograft mouse model was established, and M-T3 was administered intratumorally. Tumor growth was monitored, and excised tumors were analyzed for expression of CD137 and proliferative activity. RESULTS: Analysis of a clinical cohort revealed a significant enrichment of M. morganii in fecal samples from CRC patients compared to healthy controls. Mechanistically, treatment with M-T3 activated the NF-κB signaling pathway and consequently was associated with upregulation of CD137 in vitro. M-T3 treatment significantly enhanced the proliferation, clonogenicity, and migration of HCT116 cells, which were effectively reversed by NF-κB pathway inhibition. In vivo, intratumoral delivery of M-T3 accelerated tumor growth in HCT116 xenografts, accompanied by elevated tumor expression of CD137 and an increase in the proliferation marker Ki-67. DISCUSSION: This work demonstrates that M. morganii promotes CRC progression via its secreted protein mixture, M-T3, through NF-κB signaling, and is associated with CD137 upregulation in tumor cells. Contrary to the classical view of CD137 as an immune costimulator, its tumor cell-intrinsic expression is associated with malignant phenotypes rather than confirmed functional causality. These findings establish a "bacterial secretome-tumor signaling axis" as a novel mechanism in microbiota-driven carcinogenesis. CONCLUSION: Collectively, our work showed that M. morganii promotes colorectal cancer progression via the secreted protein mixture M-T3, which activates the NF-κB signaling pathway and is associated with upregulation of CD137. These findings suggest a potential bacterial secretome-tumor signaling link in CRC. Further studies are required to identify the upstream sensing mechanism of M-T3 and determine the functional contribution of CD137 to M-T3-induced malignant phenotypes.