Figure 3. TAM- and MDSC-dependent mechanisms driving tumor progression.

TAMs and MDSCs sustain tumor growth, progression, and dissemination by promoting immune dysfunction (green slices) but also by nonimmune-related mechanisms (yellow slices). (A) TAMs alter immune responses in tumor-bearing hosts by four main mechanisms: 1) inhibition of T cell activation; 2) inhibition of T cell viability; 3) promotion of Treg induction and recruitment; and 4) consumption of metabolites essential for T cell fitness. TAMs promote tumor angiogenesis and vasculogenesis by the release of VEGF and WNT7β, which favor the generation of new blood vessels and sustain metastasis. Finally, TAMs maintain the cancer cell reservoir by secreting IL-6 and TNF-α and produce MFG-E8 to protect CSCs from chemotherapy. (B) MDSCs inhibit the immune response in tumor-bearing mice by four processes: 1) MDSCs drive the differentiation of immune cells toward regulatory cells; 2) MDSCs interfere with T cell migration and viability; 3) MDSCs alter T cell fitness by turning on intracellular ARG1, NOS2, and NOX2 expression to produce NO, ROS, and RNS (ONOO^–, O₂^–, H₂O₂); and 4) MDSCs deplete essential metabolites for T lymphocyte fitness. MDSCs can also promote tumor angiogenesis and vasculogenesis via VEGF and MMP9 secretion. MDSCs produce elevated levels of TGF-β and HGF in primary tumors, inducing EMT, and secrete versican in the metastatic niche, promoting MET. Finally, MDSCs maintain tumor cell stemness by both IL-1RA production and by inducing the upregulation of miR-101 in cancer stem cells. cGMP, cyclic GMP; βcat, β-catenin; N, nitrosylated/nitrated; Tcf, HNF1 homeobox A.