2. Academic Validation
  3. FomA-Containing Outer Membrane Vesicles of Fusobacterium Nucleatum Facilitate Bladder Cancer Lymphatic Metastasis via IL-6-Dependent M2b Macrophage Polarization

FomA-Containing Outer Membrane Vesicles of Fusobacterium Nucleatum Facilitate Bladder Cancer Lymphatic Metastasis via IL-6-Dependent M2b Macrophage Polarization

  • Adv Sci (Weinh). 2026 Apr;13(23):e23256. doi: 10.1002/advs.202523256.
Wentai Shangguan 1 2,  Weijia Li 1,  Wenxue Huang 1,  Jilin Wu 3,  Yao Yu 1,  Yiyao Huang 4,  Lin Yang 1,  Ming Xie 1,  Qishen Yang 1,  Jun Zheng 1,  Yuexuan Zhu 1,  Qi Sun 1,  Biao Li 1,  Leqian Li 1,  Zongwei Wang 5,  Jie Zhao 6,  Peng Wu 1,  Bisheng Cheng 1 5 7 8
Affiliations

Affiliations

  • 1 Department of Urology, Nanfang Hospital,Southern Medical University, Guangzhou, China.
  • 2 Department of Urology, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
  • 3 Department of Urology, Peking University People's Hospital, Beijing, P. R. China.
  • 4 School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, Guangdong, P. R. China.
  • 5 Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, Boston, Massachusetts, USA.
  • 6 NMPA Key Laboratory For Research and Evaluation of Drug Metabolism, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.
  • 7 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, P. R. China.
  • 8 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, P. R. China.
PMID: 41684282 DOI: 10.1002/advs.202523256
Abstract

Outer membrane vesicles (OMVs) derived from the microbiota have emerged as key modulators of tumor progression and the immune microenvironment. However, the role of urinary microbiota and their associated OMVs proteins in the metastatic processes of bladder Cancer (BCa) remains insufficiently understood. In this study, we investigated the impact of urinary microbiota on BCa progression and identified potential biomarkers within the urinary microbiome. We identified Fusobacterium nucleatum (F. nucleatum) as a predominant member of the urinary microbiota. Proteomic analysis of F. nucleatum OMVs revealed the outer membrane protein FomA as the most abundant component. A FomA-deficient F. nucleatum mutant strain was generated to assess the relationship between FomA and lymph node (LN) metastasis. Mechanistically, FomA-containing OMVs directly engage Toll-like Receptor 2 (TLR2), triggering the NF-κB signaling pathway and upregulating interleukin-6 (IL-6) expression. Elevated IL-6 induces M2b macrophage polarization, which subsequently promotes the release of VEGF-C to facilitate LN metastasis. Furthermore, we identified pinocembrin, a natural flavonoid, as a potent inhibitor of the FomA-TLR2 interaction, effectively suppressing BCa progression. Collectively, our findings uncover a previously unrecognized microbiota-driven mechanism by which F. nucleatum-derived OMVs reprogram the tumor immune microenvironment toward a pro-metastatic state and highlight FomA as a promising therapeutic target.

Keywords

IL‐6; M2b macrophage; bladder cancer; fomA; fusobacterium nucleatum; lymph node metastasis; vegf‐C.

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