Intra-tumoral microbiota and host genotype cooperatively shape neutrophil antitumor activity in colorectal cancer

The role of tumor-associated neutrophils (TANs) infiltrating colorectal cancers is still debated.Here we unravel that TAN recruitment and functions are modulated by intra-tumoralmicrobiota and only defined bacterial species are able to unleash TANs’ antitumor potential.Fusobacterium nucleatum (Fn) promotes production of neutrophil-recruiting chemokines bytumor cells and enhances neutrophil migration more efficiently than Bacteroides fragilis (Bf).Importantly, Fn, but not Bf, triggers neutrophils to release cytotoxic proteins showingtumoricidal activity in vitro and in xenograft models. Mechanistically, these antitumor effectsare elicited upon Fn binding to Siglec-14 expressed by neutrophils but are impaired uponSiglec-14 blockade or loss-of-function polymorphism. Supporting these findings, in humanCRCs, elevated Fn loads, high TANs densities, and expression of wild-type, but notpolymorphic, Siglec-14 allele, correlate with improved patient survival.Our findings identify microbiota composition and host genetic background as criticaldeterminants of TAN functional profiles and offer insights into neutrophil-targetedtherapeutic strategies in CRC.