Neutrophil senescence imparts sexual dimorphism in cancer

Sex disparities is epidemiologically linked to non-reproductive cancer exampled by the difference of bladder cancer incidence, prognosis and mobility between sexes. In the past, great attention has been paid to the effectors of sex chromosome associated genes and hormones, yet how the intrinsic microbiome difference between the sexes orchestrates immune system to influence the sex disparities of tumors remains unclear. Here, we integrated cross-species single-cell RNA sequencing (scRNA-seq) data of human and mouse bladder tumor-infiltrating immune cells and identified a lipocalin-2+ (LCN2+) senescence-like neutrophil (LSLN) subpopulation that exclusively present in the male tumor microenvironment, and predict a poor prognosis for male patients with bladder cancer. By selective depletion of this senescence-like neutrophils, we demonstrate that LSLNs exert a potent immunosuppressive function to impair T cell activity, and thereby limiting anti-tumor immunity. More importantly, the differently enriched LSLNs between sexes was attributed to a gut anaerobic bacterium, Alistipes shahii, which populates in females rather than males. We show that A. shahii-associated metabolite lurasidone directly target LCN2 in LSLNs. By freeing Fe2+, lurasidone induced ferroptosis; thus, eliminating this neutrophil subset and promoting antitumor immunity in females. While males lacking A. shahii and its associated metabolite lurasidone led to the survival of LSLNs. Together, our findings unveil a novel mechanism involving the microbiota-lurasidone-LCN2 circuit, which operates independently of sex hormones and chromosomes, contributing to the sexual dimorphism in bladder cancer. Importantly, these findings underscore the therapeutic potential of lurasidone, an FDA-approved drug, for male cancer patients.性别差异与非生殖系统癌症存在流行病学关联，以膀胱癌的性别间发病率、预后与患病率差异为例。既往研究多聚焦于性染色体相关基因与激素的调控作用，然而性别间固有菌群差异如何通过调控免疫系统以影响肿瘤的性别差异，目前仍未阐明。本研究整合了人与小鼠膀胱癌肿瘤浸润免疫细胞的跨物种单细胞RNA测序（single-cell RNA sequencing, scRNA-seq）数据，鉴定出一类仅存在于男性肿瘤微环境中的脂质运载蛋白2阳性（lipocalin-2+, LCN2+）衰老样中性粒细胞（LSLN）亚群，且该亚群与膀胱癌男性患者的不良预后相关。通过特异性清除该衰老样中性粒细胞，本研究证实LSLNs具有强大的免疫抑制功能，可损伤T细胞活性，进而削弱抗肿瘤免疫应答。更为重要的是，性别间LSLNs富集程度的差异，可归因于一种肠道厌氧菌——沙氏别样杆菌（Alistipes shahii），该菌在女性肠道中定植而非男性。研究发现，A. shahii相关代谢产物鲁拉西酮（lurasidone）可直接靶向LSLNs中的LCN2。鲁拉西酮通过游离Fe²+诱导铁死亡，从而清除该中性粒细胞亚群，增强女性个体的抗肿瘤免疫应答。而男性体内缺乏A. shahii及其相关代谢产物鲁拉西酮，导致LSLNs得以存活。综上，本研究揭示了一条全新的调控轴：菌群-鲁拉西酮-LCN2调控轴，该通路不依赖于性激素与性染色体，参与膀胱癌的性别二态性形成。值得注意的是，本研究结果证实，经美国食品药品监督管理局（Food and Drug Administration, FDA）批准的药物鲁拉西酮，对男性癌症患者具有潜在治疗价值。