Myeloid-derived suppressor cells (MDSCs) enable metastasis by inhibiting innate and adaptive immune responses. During pre-metastatic niche formation, MDSCs lack their T-cell immunosuppressive function; instead, they exhibit an enhanced migratory ability and pro-angiogenic qualities, resulting in the better engraftment of circulating tumor cells. Emerging studies reveal that angiotensin-converting enzyme (ACE) activity affects myeloid cell populations’ proliferation, differentiation, and maturation. Furthermore, pre-clinical findings indicate that angiotensin-converting enzyme inhibitors (ACEi) deplete both circulating and tumor-infiltrating myeloid cells, mainly targeting the monocytic-MDSCs. Thus, MDSCs are currently considered potential druggable targets for ACE inhibitors, offering a new therapeutic window for immune cell modulation to prevent metastatic outgrowth and recurrence due to a dual mechanism that decreases tumor angiogenesis and reverses tumor microenvironment immunosuppression.