Intratumoral microbiota and host genotype cooperatively shape neutrophil cytotoxic functions in colorectal cancer.

The role of tumor-associated neutrophils (TANs) infiltrating colorectal cancers (CRCs) is still debated. Here, we unravel that TAN recruitment and functions are modulated by intratumoral microbiota and only defined bacterial species can unleash neutrophil cytotoxic potential. Fusobacterium nucleatum promotes the production of neutrophil-recruiting chemokines by tumor cells and enhances neutrophil migration more efficiently than Bacteroides fragilis. Importantly, Fusobacterium nucleatum, but not Bacteroides fragilis, triggers neutrophils to release cytotoxic proteins showing tumoricidal activity in vitro and in xenograft models. Mechanistically, these effects are elicited upon Fusobacterium nucleatum binding to sialic-acid-binding immunoglobulin-like lectin (Siglec)-14 expressed by neutrophils but are impaired upon Siglec-14 blockade or loss-of-function polymorphisms. Supporting these findings, in human CRCs, elevated Fusobacterium nucleatum loads and high TAN densities correlate with improved prognosis, whereas lack of Siglec-14 expression is associated with reduced patient survival. Our findings identify microbiota composition and host genetic background as critical determinants of neutrophil functional profiles, offering insights into neutrophil-targeted therapeutic strategies in CRC.