Sex of central neurons controls intestinal niche signalling to drive sex differences in stem cell activity and cancer susceptibility.

Sex differences in cancers arising in non-reproductive organs are widespread. While sex hormones and the intrinsic sexual identity of cancer cells are well-established contributors, it is unknown whether other mechanisms are involved. Here, we reveal an unexpected source of sex-biased cancer vulnerability in a Drosophila model of tumorigenesis. By combining genetically induced tumours with tissue- and cell type-specific sex reversals, we show that sex differences in oncogenesis can arise independently of both gonadal hormone signalling and the sexual identity of tumour cells themselves. Unexpectedly, we find that a sexually dimorphic neuronal circuit, classically associated with mating behaviour, is both necessary and sufficient to drive sex-biased intestinal tumorigenesis. The sex of these gut-innervating neurons controls tumour growth by stimulating local production of an insulin-like growth factor in the visceral muscles, a key component of the intestinal stem cell niche. Our findings reveal a previously unrecognised class of tumour-promoting input: the sex of central neurons can reprogram peripheral tumour-supportive environments. Under physiological conditions, this brain-gut pathway also modulates stem cell activity and organ size in a sex-specific manner to promote reproduction. Our work opens a new line of inquiry into how neuronal sex, particularly within the brain-gut axis, shapes physiology and disease, a field still predominantly studied in a male-only context.