Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity, implicated in various pathological conditions, including cancer and autoimmune diseases. Recent studies have highlighted key distinctions between MDSCs and classical neutrophils and monocytes, focusing on their genomic and metabolic characteristics. These characteristics shape MDSC function and offer potential therapeutic targets, particularly in cancer and autoimmune diseases. MDSCs are classified into granulocytic/polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), with PMN-MDSCs emerging from neutrophil progenitors and M-MDSCs from monocyte precursors. Pathological activation of MDSCs is driven by persistent stimulation of the myeloid cell compartment, leading to the acquisition of specific genomic, proteomic, and metabolic features. These features include upregulation of STAT3, expression of S100A8/A9, and metabolic reprogramming, such as increased lipid accumulation and altered glucose metabolism. MDSCs play a crucial role in the formation of the premetastatic niche, promoting tumor cell engraftment and metastasis. Therapeutic approaches targeting MDSCs include blocking their recruitment, depleting them, and reprogramming their function to enhance antitumour immunity. In autoimmune diseases, MDSCs can have both protective and detrimental effects, depending on the disease context. Overall, understanding the distinct characteristics and functions of MDSCs is essential for developing effective therapeutic strategies.Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity, implicated in various pathological conditions, including cancer and autoimmune diseases. Recent studies have highlighted key distinctions between MDSCs and classical neutrophils and monocytes, focusing on their genomic and metabolic characteristics. These characteristics shape MDSC function and offer potential therapeutic targets, particularly in cancer and autoimmune diseases. MDSCs are classified into granulocytic/polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs), with PMN-MDSCs emerging from neutrophil progenitors and M-MDSCs from monocyte precursors. Pathological activation of MDSCs is driven by persistent stimulation of the myeloid cell compartment, leading to the acquisition of specific genomic, proteomic, and metabolic features. These features include upregulation of STAT3, expression of S100A8/A9, and metabolic reprogramming, such as increased lipid accumulation and altered glucose metabolism. MDSCs play a crucial role in the formation of the premetastatic niche, promoting tumor cell engraftment and metastasis. Therapeutic approaches targeting MDSCs include blocking their recruitment, depleting them, and reprogramming their function to enhance antitumour immunity. In autoimmune diseases, MDSCs can have both protective and detrimental effects, depending on the disease context. Overall, understanding the distinct characteristics and functions of MDSCs is essential for developing effective therapeutic strategies.