We revealed a two-step underlining mechanism whereby P. anaerobius first interacts with CRC cells to promote CXCL1-driven MDSC chemotaxis into CRC and then by direct P. anaerobius–MDSC interplay via lytC_22–Slamf4 to endow MDSCs with an immunosuppressive function. This evidence concerns the gene CD244 and colorectal carcinoma.