Neutrophil senescence imparts sexual dimorphism in cancer
Description
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.