In conclusion, the current findings demonstrate that S100A9 plays a critical role in regulating M2-like Mφ polarization in Fn-infected CRC microenvironment, and targeting TLR4/NF-κB/S100A9 cascade may attenuate the immunosuppressive effect and serve as promising immunotherapy strategy for Fn-associated CRC. Here, FN1 is linked to colorectal carcinoma.