Concomitant NAFLD Facilitates Liver Metastases and PD-1Refractory by Recruiting MDSCs via CXCL5/CXCR2 in Colorectal Cancer

BACKGROUND & AIMS: Both nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effects of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been de fi nitively elucidated. METHODS: We observed the effect of concomitant NAFLD on CRLM in the mouse model and explored the underlying mechanisms of speci fi c myeloid-derived suppressor cells (MDSCs) recruitment and then tested the therapeutic application based on the mechanisms. Finally we validated our fi nd- ings in the clinical samples. RESULTS: Here we prove that in different mouse models, NAFLD induces F4/80 + Kupffer cells to secret chemokine CXCL5 and then recruits CXCR2 + MDSCs to promote the growth of CRLM. CRLM with NAFLD background is refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the in fi ltration of CXCR2 + MDSCs, as well as the hazard of liver metastases in CRC patients. CONCLUSIONS: Collectively, our fi ndings highlight the signi fi cance of selective CXCR2 + /CD11b + /Gr-1 + subset myeloid cells in favoring the development of CRLM with NAFLD background and identify a pharmaceutical medicine that is already available for the clinical trials and potential treatment. (Cell Mol Gastroenterol Hepatol 2024;18:101351; https://doi.org/10.1016/j.jcmgh.2024.04.008)