Metastatic disease is the primary cause of death in patients with cancer; thus, identifying new therapeutic targets to stop the spread of cancer is needed. Triple-negative breast cancer (TNBC) is an extremely metastatic subtype with the highest death rate in breast cancer and limited therapeutic options. Myeloid-Derived Suppressor Cells (MDSCs) are a heterogeneous and poorly defined group of tumour-infiltrating myeloid progenitors that can promote cancer progression and metastasis. Recently, it has been suggested that MDSCs contribute the colonisation of residual tumour cells, but the molecular drivers that trigger MDSC differentiation towards a pro-metastatic phenotype remain poorly understood. To understand the role of MDSC in metastasis we have performed, single-cell RNAseq and scATACseq of metastatic lungs from a highly aggressive TNBC model as well as a non-metastatic TNBC model. We found a key subpopulation of granulocytic MDSC that was exclusive to the metastatic model and expressed genes involved in the suppression of the adaptive immune system. These metastatic granulocytic MDSCs (met-gMDSCs) resemble bone marrow progenitors and are epigenetically distinct from mature neutrophils. Next, to module the differentiation of met-gMDSCs, we used low-dose epigenetic therapy: 5’Azacytidine (DNA demethylating agent) and Entinostat (HDAC inhibitor). Mice treated with 5’Azacytidine and Entinostat had less metastasis and reduced splenomegaly. scRNAseq analysis of metastatic lungs showed a reduced ratio of met-gMDSCs and downregulation of immunosuppressive and pro-oncogenic genes in the neutrophil population, while pro-inflammatory genes associated with anti-cancer activity were upregulated. This treatment did not cause neutropenia, in line with previous reports in clinical trials. In conclusion, low-dose epigenetic therapy reprogrammed the cancer-associated myeloid differentiation to reduce met-gMDSC and promote an anti-cancer phenotype in neutrophils. These findings open a new treatment avenue for metastatic TNBC, where combining low-dose epigenetic therapy with immune checkpoint inhibitors, could block the immunosuppressive signals from the myeloid cells, and increase their efficacy.