Fig. 2

Interconnections between metabolism, cancer-related inflammation, myelopoiesis, and cancer therapy. Obesity and adipose tissue macrophages (ATMs) promote myeloid cell expansion by releasing various inflammatory cytokines and adipokines that activate selected transcriptional activities (PARs, RORC1/RORγ, and C/EBPβ) affecting HSC proliferation and differentiation. This myelopoietic boost is amplified by cancer cells that release additional myelopoietic factors, including CSFs, IL-1, IL-17, and PGE2. These factors induce myelopoiesis through the upregulation of specialized transcription factors (i.e., p50 NF-κB, STAT3, and PU-1). The production of adenosine, VEGF, and IL-10 by cancer cells induces the tumor-promoting phenotype (IL-10^high/IL-12^low) of iDCs. The emerging myeloid populations are then recruited to the tumor site, where they acquire suppressor phenotypes (TAMs, TANs, MDSCs, and iDCs) and establish an immunosuppressed tumor microenvironment (TME). The tumor site actively hinders the activation of T lymphocytes through the depletion of amino acids, orchestrated by both infiltrating myeloid suppressor cells and cancer cells that express immunosuppressive enzymes (IDO, iNOS, and Arg1). IDO activity, in particular, results in the production of the immunosuppressive catabolite kynurenine (Kyn), which is capable of inducing the expansion of regulatory T (Treg) cells. Further expression of immune checkpoint ligands (i.e., PD-L1) by myeloid suppressor cells contributes to the inhibition of antitumor immunity. The metabolic consequences of obesity also drive the transition of macrophages from “M2-like” to “M1-like” activation, contributing to inflammation-driven insulin resistance (IR). Of note, both obesity and select chemotherapeutics (i.e., irinotecan, etoposide, and platinum) can induce IR, interfere with the energetic balance and affect T cell activation. However, chemotherapy can also enhance antitumor immunity by promoting the immunogenic cell death (ICD) of cancer cells (i.e., anthracyclines, DNA-damaging agents) and by depleting MDSCs (i.e., docetaxel, gemcitabine, and 5-fluorouracil). In line with this, the inhibition of FAO significantly decreases FA uptake and inhibits the immunosuppressive function of MDSCs. Globally, the intersection of the host’s metabolic status, tumor metabolism, cancer inflammation and the quality of myelopoietic output strongly influences the response to therapy. ICD immunogenic cell death, IR insulin resistance, FAO fatty acid oxidation, FA fatty acid