Loss of NDRG2 in Liver Microenvironment Inhibits Cancer Liver Metastasis by Regulating Tumor Associate Macrophages Polarization

The liver is the predominant metastatic site for several types of malignancies. Tumor-associated macrophages (TAMs) in the liver play crucial roles in the metastasis process. Shifting tumor-promoting M2-like TAMs toward the M1-like phenotype, which exerts tumor suppressor functions via phagocytosis and the secretion of inhibitory factors, may be a potential therapeutic strategy for liver cancer metastasis treatment.We first cloned NDRG2 (N-myc downstream-regulated gene 2) and verified its tumor suppressor role in multiple solid tumors, including colorectal cancer and hepatocellular carcinoma. However, its role in the tumor-associated liver microenvironment, especially in TAMs, has not been illustrated. By establishing a liver cancer metastasis model in wild-type (WT) and Ndrg2 knockout (Ndrg2-/-) mice, we found that the loss of the tumor suppressor Ndrg2 in liver microenvironment significantly suppressed the growth of liver colonies. In addition, this process was accompanied by a higher proportion of M1-like TAM infiltration in Ndrg2-/- mice. Interestingly, bone marrow (BM) transplantation revealed that BM-derived macrophages (BMDMs) rather than liver resident Kupffer cells were responsible for the inhibitory effect. We further demonstrated that loss of Ndrg2 influenced TAM polarization via the NF-κB pathway. Inhibition of IκBα phosphorylation in cancer cell-conditioned medium-stimulated BMDMs decreased M1 marker expression in Ndrg2-/- macrophages. Finally, in vitro, invasion, migration, and proliferation assays confirmed that NF-κB participated in the tumor suppressor function of Ndrg2-/- macrophages. Collectively, our findings highlight the role of NDRG2 in the regulation of TAM polarization and its function in promoting cancer liver metastasis.