LAUSR

Abstract Metabolic reprogramming is a hallmark of solid cancers. Macrophages as major constituents of immune system take important roles in regulation of tumorigenesis. Pro-tumor M2 macrophages preferentially use oxidative phosphorylation (OXPHOS) to meet their metabolic demands, while anti-tumor M1 macrophages use glycolysis as their dominant metabolic source. Dysregulation in metabolic systems is a driving force of skewing macrophages from M1 toward M2 phenotypical state. Hyperactive M1 macrophages, for instance, release metabolic products that are contributed to M2 macrophage polarization. Thus, metabolic remodeling through reinstating normalization in metabolic systems can be an effective tool in cancer therapy. The key focus of this review is over metabolic systems in macrophages and factors influencing their metabolic acquisition and reprogramming in cancer, as well as discussing bout strategies to adjust macrophage metabolism and reeducation toward M1-like phenotype. Highlights M1 and M2 macrophages evolve diverse metabolic priorities. Strike for utilizing TME metabolic sources hampers M1 macrophage polarization. Hyperactive M1 macrophages skew TME macrophages toward M2 phenotype. Shifting TAM metabolism more into glycolysis is important therapeutically. Transient HIF-1low condition favors M1 phenotypical acquisition, whereas consistent HIF-1/lactate high favors M2 polarization. Plain Language Summary Tumor-associated macrophages (TAMs) are one of the most frequent immune cells infiltrated into tumor area. The cells have intense cross taking with other cells of tumor stroma. The presence of immunosuppressive tumor microenvironment (TME) is contributed to the higher and more potent interactions between M2 macrophages. Metabolic abnormality is a tumor hallmark. Tumor cells harness metabolic byproducts in order for taking a control over immune cells. Enhanced mitochondrial oxidative phosphorylation is a promoter of pro-tumor M2 macrophage polarization, whereas enhanced glycolysis is a promoter of anti-tumor M1 polarization. Lack of sufficient O2 and nutrient sources in stroma of solid tumors account for a shift in tumor cell metabolism toward glycolysis, which is indicative of limited energy sources for macrophages to take glycolysis and polarizing toward M1 phenotype. Besides, hyperactive M1 macrophages due to displaying high glycolytic activity and the subsequent release of high lactate into the TME will lead to the highly acidified TME which subsequently causes deviation in phenotype profiling of macrophages and skewing them toward pro-tumor phenotype. Vascular maturation or normalization will adjust O2 and nutrient conditions in the TME and is a key contributor to the M1 predilection. Exploiting such strategy is not in bias with the predilection glycolysis route for M1 polarization. Instead, when nutrients are available in the tumor ecosystem, metabolic sources are not taken from M1 and other anti-tumor cells of immune system, so they will be more active for acting against tumor cells and dampening their activities. Graphical Abstract