Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment

Abstract

The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype. M2-like macrophages depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. However, this metabolically reprogrammed phenotypic switch in macrophages remained a mystery for a while. Therefore, through this review, we tend to describe how macrophage immunometabolism determines macrophage phenotypes and functions in tumor microenvironments (TMEs). Furthermore, we have discussed how metabolic reprogramming in TAM can be used for therapeutic intervention and drug resistance in ovarian cancer.

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

“…26 42-47 The TAM compartment undergoes extensive remodeling of core energy metabolism during tumor progression (table 1). [48][49][50] In hypoxic TMEs, including the TME in EOC, the cells prefer to use glycolytic metabolism. The accumulation of lactic acid in TAMs and other cells present in the TME that use glycolysis results in the differentiation of TAMs into cells characterized by a tumorpromoting phenotype.…”

Targeting acidic pre-metastatic niche in lungs by pH low insertion peptide and its utility for anti-metastatic therapy

“…Tumor acidification is thought to be mainly resulting from lactate overproduction by highly proliferative tumor cells which utilize glycolysis independent of oxygen availability. Meanwhile, some types of stromal cells in tumor undergo metabolic shift toward glycolysis which is associated with their pro-tumorigenic functions ( 48 , 49 ). In line with the findings about glycolysis reprogramming in non-cancerous host stromal cells, we demonstrated the upregulated glucose metabolism and localization of pHLIP in AT2 cells and some CD45 + hematopoietic cells which may contribute to formation of the acidic environment by supplying the acidic metabolite, lactate.…”

Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer

“…It is plausible that in tumors with PTEN loss, reduced infiltration of macrophages also impedes the process of tumor antigen cross presentation to CD8+T cells and may undergo metabolic reprogramming. 30 31 Their decreased chemokine expression in the TIME may thus further contribute to lower infiltration of immune cells contrasting tumors with BRCA1 loss. Other mechanisms compounding this effect such as Pten -loss associated hypoxia contribute to an ‘immune excluded’ phenotype observed in other solid tumor cancers, may also be relevant within HGSC tumors.…”

“…Several mechanisms within the complex TIME of HGSC may indeed contribute to an M2-dominated state. 30 31 Most relevant to our study is the reduced feed-forward loop activation of STAT1 and CXCL10 that may act in parallel to other cancer cell intrinsic mechanisms. 38 39 In BRCA1 -deficient tumors, a significantly active STAT1/CXCL10 axis in both the cancer and tumor infiltrating immune cells has been widely reported.…”