Fig. 1

Protumor reprogramming of myeloid cells. Tumor-derived factors (TDFs), including cytokines, myeloid growth factors and metabolites, induce transcriptional activities (i.e., expression of cEBPβ, STAT3, p50, and RORC1/RORγ) guiding the enhanced proliferation and lymphoid to myeloid switch of HSCs. In parallel, activation of CSF-dependent induction of iNAMPT provides enhanced NAD-dependent activation of the sirtuin 1 deacetylase, which inhibits the HIF-1α-dependent and p65 NF-κB-dependent transcription of CXCR4. Deactivation of the anchoring signal CXCR4 mobilizes myeloid cells from the bone marrow, allowing peripheral expansion of myeloid populations (monocytes, neutrophils, MDSCs, and DCs). These cells reach the tumor site through the circulation and infiltrate the tumor tissue in response to tumor-derived chemotactic signals (TDCFs) (i.e., CXCL2, CXCL8, CCL2, S100, VEGF, C5a, and CSF1). In particular, DCs and MDSCs enter the secondary lymphoid organs (lymph nodes and spleen), eliciting inhibitory signals to T cells. Once in the tumor, myeloid cells undergo a further step of reprogramming in response to inhibitory molecules (IL-10, TGFβ, adenosine, NO, and PD-L1) and microenvironmental conditions (low glucose levels, hypoxia, and low pH), terminally differentiating into myeloid suppressor cells (TAMs, TANs, MDSCs, and immature DCs). Overall, the tumor-dependent reprogramming of myeloid populations has to be considered a multistep program, which comprises induction of emergency myelopoiesis (enhanced proliferation and the “lymphoid to myeloid” switch), mobilization to the periphery and final intratumor reprogramming. Common myeloid precursors (CMPs), hematopoietic stem cells (HSCs), tumor-derived factors (TDFs), immature DCs (iDCs)