Myeloid-derived suppressor cells (MDSCs) comprise a critical component of the tumor environment and CXCR2 reportedly plays a key role in the pathophysiology of various inflammatory diseases. Here, CXCR2 expression on granulocyte and macrophage progenitor cells (GMPs) was found to participate in myeloid cell differentiation within the tumor environment. In CXCR2-deficient tumor-bearing mice, GMPs exhibited fewer macrophage and dendritic cell progenitor cells than wild-type tumor-bearing mice, thereby decreasing monocytic MDSCs (mo-MDSCs) expansion. CXCR2 deficiency increased SAP18 expression in tumor-bearing mice, which reduced STAT3 phosphorylation through restraining ERK1/2 activation. Our findings reveal a critical role for CXCR2 in regulating hematopoietic progenitor cell differentiation under tumor conditions, and SAP18 is a key negative regulator in this process. Thus, inhibiting CXCR2 expression may alter the tumor microenvironment and attenuate tumor progression.