2. Academic Validation
  3. Microbiota-shaped neutrophil senescence regulates sexual dimorphism in bladder cancer

Microbiota-shaped neutrophil senescence regulates sexual dimorphism in bladder cancer

  • Nat Immunol. 2025 May;26(5):722-736. doi: 10.1038/s41590-025-02126-6.
Qingchen Zhu # 1,  Guiheng Zhang # 1,  Ming Cao # 2,  Huan Huang # 1,  Dan He 3,  Zhongsheng Zang 3,  Jing Xing 4,  Ming Zhan 5,  Siyu Pei 1,  Xiuyu Deng 1,  Juan Li 6,  Guangxun Meng 6,  Jing Xu 1,  Dongfang Dai 7,  Guohong Hu 1,  Mingyue Zheng 4,  Chenli Liu 8,  Jun Qin 9,  Yichuan Xiao 10
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 5 Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, State Key Laboratory of Medical Genomics, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Shanghai Institute of Immunity and Infection, University of Chinese Academy of Sciences, Shanghai, China.
  • 7 Department of Radiotherapy, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, China.
  • 8 Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China. cl.liu@siat.ac.cn.
  • 9 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. qinjun@sibs.ac.cn.
  • 10 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. ycxiao@sibs.ac.cn.
  • # Contributed equally.
PMID: 40217111 DOI: 10.1038/s41590-025-02126-6
Abstract

Sex disparities have been epidemiologically demonstrated in non-reproductive cancers, yet how the sex-specific intrinsic microbiome orchestrates the immune system to affect these disparities is unclear. Here we identify a subpopulation of RETNLG+LCN2+ senescence-like neutrophils (RLSNs) that preferentially accumulate in the male tumor microenvironment and exert a strong immunosuppressive effect to limit antitumor immunity, resulting in poor prognosis for patients with bladder Cancer. This difference in enrichment of RLSNs between sexes can be attributed to intestinal bacterium Alistipes shahii, which preferentially populates in females rather than males. A. shahii-associated metabolite lurasidone directly targets iron sequestrator LCN2 in RLSNs. By freeing Fe2+, lurasidone induces Ferroptosis, thereby eliminating RLSNs and promoting antitumor immunity in females. In males lacking A. shahii and lurasidone, RLSNs have a survival advantage. Together, these findings demonstrate that a microbiota-lurasidone-LCN2 circuit regulates sexual disparity in bladder Cancer and indicates the therapeutic potential of lurasidone for male Cancer patients.

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