The tumor microenvironment (TME) is a complex and dynamic network comprised of tumor cells, surrounding cellular components, various signaling molecules, and the stroma. Myeloid-derived suppressor cells (MDSCs) are pivotal players in the immunosuppressive landscape of the TME, effectively hindering antitumor immune responses and facilitating tumor progression. Originating from pathologically activated myeloid precursors and relatively immature myeloid cells, MDSCs retain plasticity to further differentiate into other myeloid cells, such as macrophages or dendritic cells, which underpins their heterogeneity and adaptability in response to the TME. In this review, we delve into the plasticity of MDSCs in the tumor microenvironment and illuminate the underlying mechanisms that enable them to modulate immune responses. Furthermore, we explore the implications of MDSCs plasticity for cancer therapy, particularly its role in enhancing the efficiency of combination treatments.