MDSCs can be targeted in one of three broadly defined ways. First, they can be directly killed. Low-dose gemcitabine, 5-fluorouracil, and TRAIL receptor ligation have shown efficacy in doing so, both clinically and preclinically. The second category of therapeutic is functional inhibition of MDSC-suppressive machinery. PDE-5 inhibitors, such as taldalafil, as well as NO-releasing aspirin and synthetic triterpenoids act effectively in this manner, in part by reducing the expression of ROS, reactive nitrogen species, and arginase, all central to the ability of MDSCs to inhibit immune responses. Finally, myelopoeisis can be skewed such that MDSC accumulation is inhibited and/or MDSCs are forcefully differentiated into more terminally differentiated, immunostimulatory myeloid cells such as DCs and macrophages. Sunitinib and ATRA have shown efficacy in these two functions, respectively.

(A) Immature myeloid cells (IMCs) with the typical phenotype of MDSCs are produced in response to inflammatory stimuli. However, these cells often lack immunosuppressive activity. They contribute to tumorigenesis by recruiting proinflammatory CD4⁺ T cells that promote epithelial cell proliferation. (B) Tumor development is associated with the expansion of cells with acquired immunosuppressive activity (MDSCs). These cells also promote tumor cell invasion and angiogenesis and neutralize tumor cell senescence. (C) In metastatic tumors, MDSCs, in addition to promoting tumor cell invasion and angiogenesis, can support EMT and differentiation of osteoclasts supporting bone resorption.

Differentiation of neutrophils and mononuclear cells in naive mice is shown by black arrows. Hematopoietic stem cells (HSC) differentiate into common myeloid progenitors (CMP), then into granulocyte-macrophage progenitors (GMP), which give rise to mature neutrophils via sequential steps of differentiation involving myeloblasts, promyelocytes, myelocytes, metamyelocytes, and band forms. Differentiation of macrophages and DCs involves macrophage/DC progenitors (MDP), DC progenitors (CDP), and pre-cDCs as well as several types of monocytes. The most prominent are Ly6C⁺ inflammatory monocytes and Ly6C^– patrolling monocytes. Differentiation of myeloid cells in tumor-bearing mice is shown by red arrows. Tumor-derived signals affect all steps of granulocytic and monocytic cell differentiation, causing expansion of pathologically activated PMN-MDSCs and Ly6C⁺ M-MDSCs. During tumorigenesis, these cells become more prevalent in bone marrow and spleen than in their nonsuppressive counterparts. M-MDSCs acquire the ability to differentiate to PMN-MDSCs and, at the tumor site, differentiate to TAMs and DCs. The dashed line represents pathways that are not yet firmly established.