RadD from Fusobacterium nucleatum Engages NKp46 to Promote Antitumor Cytotoxicity

Abstract Fusobacterium nucleatum, a Gram-negative bacterium implicated in periodontal disease, has emerged as a contributor to tumor progression in various cancers. Whether the presence of Fusobacterium nucleatum inhibits tumor progression is largely unknown. Here, we identify a subspecies-specific interaction between F. nucleatum and the natural killer (NK) cell receptor NKp46. Analysis of TCGA datasets revealed that the co-occurrence of F. nucleatum and high NKp46 expression correlates with improved survival in head and neck cancers but not in colorectal cancers. Using binding assays, we demonstrate that both human NKp46 and its murine ortholog, Ncr1, directly recognize the fusobacterial adhesin RadD. Genetic deletion of radD or blockade of NKp46 significantly impaired NK cell-mediated cytotoxicity in vitro and promoted tumor growth. In vivo infection with F. nucleatum accelerated tumor progression, with an exacerbated effect observed in the absence of RadD or NKp46. These findings highlight RadD as a critical ligand for NKp46 and establish the NKp46–RadD axis as a key interface in host–microbe–tumor interactions, offering a novel target for immunotherapeutic intervention in cancer influenced by microbial factors.