Abstract
Myeloid cells are a key determinant of tumor progression and patient outcomes in a range of cancers and are therefore being actively pursued as targets of new immunotherapies. The recent use of high-dimensional single-cell approaches, e.g., mass cytometry and single-cell RNA-sequencing (scRNA-seq) has reinforced the predominance of myeloid cells in the tumor microenvironment and uncovered their phenotypic diversity in different cancers. The cancerous metabolic environment has emerged as a critical modulator of myeloid cell functions in anti-tumor immunity versus immune suppression and immune evasion. Here, we discuss mechanisms of immune-metabolic crosstalk in tumorigenesis, with a particular focus on the tumor-associated myeloid cell’s metabolic programs. We highlight the impact of several metabolic pathways on the pro-tumoral functions of tumor-associated macrophages and myeloid-derived suppressor cells and discuss the potential myeloid cell metabolic checkpoints for cancer immunotherapy, either as monotherapies or in combination with other immunotherapies.
Highlights
Macrophages are key regulators of tissue homeostasis and acquire niche-dependent programming that results in distinct phenotypes and functions across tissues [1]
We focus on recent studies exploring the immunometabolism of macrophages in vivo, in the context of the cancerous tumor microenvironment (TME)
We describe the metabolic crosstalk between myeloid cells, cancer cells, and other cells in the TME and highlight new findings on the myeloid cell metabolism that diverge from the M1/M2 immunometabolism paradigms
Summary
Macrophages are key regulators of tissue homeostasis and acquire niche-dependent programming that results in distinct phenotypes and functions across tissues [1]. In contrast to the M1/M2 immunometabolism paradigm, more recent studies have shown that immunosuppressive TAMs and MDSCs are highly glycolytic, and that aerobic glycolysis, HIF-1α activity and succinate accumulation in the TME, promote their immunosuppressive phenotypes and functions. Alexander et al demonstrated that the myeloid-specific deletion of the circadian clock regulator Bmal, led to impaired macrophage mitochondrial metabolism, the accumulation of mitochondrial reactive oxygen species (mROS) and succinate, HIF-1α stabilization and enhanced aerobic glycolysis Such an aberrant HIF-1α activation in TAMs promoted the TAM-pro-tumoral function and tumor development [15]. TME lactate accumulation hypoxia-induced factor (HIF)-1a, the tumor cell’s upregulation of aerobic glycolysis TAMs and MDSCs accumulate lipid droplets in cytosolic vesicles and appear to rely on lipid metabolism and fatty acid oxidation for their pro-tumoral functions
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