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Myeloid Derived Suppressor Cells (MDSCs) are a heterogeneous immune population found within the tumour microenvironment (TME). We sought to explore the potential role of microenvironment components on the suppressive behaviour, development and maintenance of MDSCs, focusing mainly on the role of the SIRPα-CD47 signalling axis. In an orthotopic melanoma model, we observed an increase in Ly6C-expressing myeloid cells (indicating monocytic-myeloid derived suppressor cells (M-MDSCs) and monocytic dendritic cells (moDC)) as tumours developed. These cells were suppressive, able to block T CD8+ cell proliferation. To model the effect of tumour-derived factors on M-MDSCs and moDCs development and function, we developed a culture system using hematopoietic stem cells cultured with GM-CSF and melanoma tumour condition media (TCM). Similar to the in vivo setting, exposure to TCM skewed the myeloid compartment towards an M-MDSC and moDC phenotype (based on Ly6C expression) that potently suppressed CD8+ T cell proliferation to a greater extent than GM-CSF induced MDSCs. Further characterisation of the TME by single-cell RNA sequencing and flow cytometry revealed specific expression of the signal-regulatory protein alpha (SIRPα) in M-MDSC and moDC cells fraction and elevated expression of its cognate ligand, CD47 by other immune cells. Thus, we investigated the impact of CD47-SIRPα interaction on MDSC function. Engagement of SIRPα on moDCs and M-MDSCs by recombinant CD47 in vitro induced intracellular signalling via SHP2, and inhibited the phagocytic capability of these cells. Moreover, persistent activation of this programme translated to an increase in their suppressive phenotype quantified by elevated expression of immune checkpoint molecules, inhibitory factors and reactive oxygen species. Knowing this axis promoted a pro-tumour, suppressive phenotype, we then investigated the consequence of its disruption on tumour growth in vivo. Neutralization of SIRPα on moDCs and M-MDSCs in established tumours resulted in a significant decrease in growth, which was driven by a reprogramming of moDCs and M-MDSCs. Disruption of the CD47-SIRPα axis was sufficient to rescue their phagocytic capability, which in turn enhanced their ability to process and present antigen to tumour infiltrating T cells. These functional changes were accompanied by metabolic adaptations. In summary, we report the CD47-SIRPα axis functions as a mechanism used to support moDC and M-MDSC suppressive function in the TME, and its disruption in early tumour-infiltrating monocyte progenitors shows potential to restore anti-tumour features of myeloid cells and in turn promote the T cell mediated anti-tumour immune response.