Cancer progression depends on a tumor-supportive microenvironment. Myeloid-derived suppressor cells (MDSCs) represent key cellular components in tumor microenvironment and have been demonstrated to facilitate tumor progression by restricting host immune responses and by sustaining the malignancy of cancer cells. CUL4B, which assembles the CUL4B-RING E3 ligase complex (CRL4B), possesses a potent oncogenic property in cancer cells by epigenetically inactivating many tumor suppressors. However, CUL4B in hematopoietic cells exerts tumor-suppressive effect by restricting the accumulation and function of MDSCs. How CUL4B regulates the function of MDSCs is not fully characterized. In the present study, we demonstrate that the enhanced growth and metastasis of transplanted tumor cells in hematopoietic or myeloid cell-specific Cul4b knockout recipient mice is mediated by increased production of IL-6 in MDSCs. CUL4B complex epigenetically represses IL-6 transcription in myeloid cells. The IL-6 produced by MDSCs renders cancer cells stem cell-like properties by activating IL-6/STAT3 signaling. This crosstalk was effectively blocked either by blocking IL-6 in MDSCs or by inhibition of STAT3 activation in tumor cells. These findings provide a new mechanistic insight into the cancer-promoting property of MDSCs.