Neutrophil senescence imparts sexual dimorphism in cancer

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.