Zhu Qingchen, Zhang Guiheng, Cao Ming, Huang Huan, He Dan, Zang Zhongsheng, Xing Jing, Zhan Ming, Pei Siyu, Deng Xiuyu, Li Juan, Meng Guangxun, Xu Jing, Dai Dongfang, Hu Guohong, Zheng Mingyue, Liu Chenli, Qin Jun, Xiao Yichuan
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.
Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nat Immunol. 2025 May;26(5):722-736. doi: 10.1038/s41590-025-02126-6. Epub 2025 Apr 11.
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 RETNLGLCN2 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 Fe, 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.
性别差异在非生殖系统癌症中已得到流行病学证实，但性别特异性内在微生物群如何调节免疫系统以影响这些差异尚不清楚。在此，我们鉴定出一类RETNLGLCN2衰老样中性粒细胞（RLSNs）亚群，其优先在男性肿瘤微环境中积累，并发挥强大的免疫抑制作用以限制抗肿瘤免疫，导致膀胱癌患者预后不良。男女之间RLSNs富集的这种差异可归因于肠道细菌沙氏阿利斯杆菌，其优先定殖于雌性而非雄性体内。沙氏阿利斯杆菌相关代谢产物鲁拉西酮直接靶向RLSNs中的铁螯合剂LCN2。通过释放铁，鲁拉西酮诱导铁死亡，从而消除RLSNs并促进雌性的抗肿瘤免疫。在缺乏沙氏阿利斯杆菌和鲁拉西酮的男性中，RLSNs具有生存优势。总之，这些发现表明微生物群-鲁拉西酮-LCN2回路调节膀胱癌中的性别差异，并表明鲁拉西酮对男性癌症患者的治疗潜力。
