A secreted protein from Hungatella hathewayi inhibits colorectal cancer by reprogramming intratumoral CD14b+ macrophages.

Gut microbiota has been widely implicated in colorectal cancer (CRC). Here, we show that H. hathewayi, a commensal bacterium previously associated with CRC, is protective against intestinal tumor growth, and gut dysbiosis in a spontaneous CRC model. H. hathewayi attenuated the growth of allografted colon carcinoma cells and suppressed CRC progression in ApcMin/+ mice, concomitant with an increased intratumoral CD14b+ tumor-associated macrophages (TAMs). Such protective effect was attributed to H. hathewayi-secreted proteins from Hh.CM, and we identified a cell wall-binding repeat-containing protein (CWBR-CP) as the key functional mediator. CWBR-CP recapitulated the tumor suppression of H. hathewayi in multiple mouse models and induced a corresponding shift toward M1-like macrophage polarization. Mechanistically, CWBR-CP directly bound to kallikrein 8 (KLK8) and downregulated its expression in macrophages. KLK8 downregulation, in turn, activated bradykinin receptor B1 (B1R), triggering the PI3K/AKT/NF-κB pathway and ultimately promoting M1 macrophage polarization.