Metabolic reprogramming by miRNAs in the tumor microenvironment: Focused on immunometabolism

Abstract

MicroRNAs (miRNAs) are emerging as a significant modulator of immunity, and their abnormal expression/activity has been linked to numerous human disorders, such as cancer. It is now known that miRNAs potentially modulate the production of several metabolic processes in tumor-associated immune cells and indirectly via different metabolic enzymes that affect tumor-associated signaling cascades. For instance, Let-7 has been identified as a crucial modulator for the long-lasting survival of CD8⁺ T cells (naive phenotypes) in cancer by altering their metabolism. Furthermore, in T cells, it has been found that enhancer of zeste homolog 2 (EZH2) expression is controlled via glycolytic metabolism through miRNAs in patients with ovarian cancer. On the other hand, immunometabolism has shown us that cellular metabolic reactions and processes not only generate ATP and biosynthetic intermediates but also modulate the immune system and inflammatory processes. Based on recent studies, new and encouraging approaches to cancer involving the modification of miRNAs in immune cell metabolism are currently being investigated, providing insight into promising targets for therapeutic strategies based on the pivotal role of immunometabolism in cancer. Throughout this overview, we explore and describe the significance of miRNAs in cancer and immune cell metabolism.

Keywords: MicroRNAs; cancer; immune cell; immunometabolism; metabolism.

Figure 1

miRNAs and control of metabolism. miRNAs have been shown to regulate many stages in metabolism through modulation of the expression of key metabolic enzymes (e.g., hexokinase-2 by miR-133), transporters (e.g., GLUT by miR195-5p), or pathways that control metabolism such as the PI3K pathway (e.g., miR-19, miR-7, and miR-139).

Figure 2

miRNAs regulate glucose metabolism in normal vs malignant cells. The diagram represents the primary alternative energy metabolism pathways in human cells and their proportionate use in normal quiescent cells and tumor and highly proliferative cells, which are depicted via varying degrees of clarity. The letter size distinguishes the frequency of recognized regulatory miRNAs, their primary mRNA targets (HK, LDHA, and HIF1), as well as particular indirect miRNA regulatory interplays with other miRNAs or pathway interactions. Modulatory connections are represented by referring arrowheads, whereas repressive interactions are represented by inhibiting arrows. The designations of pathways and metabolites are emphasized in bold and thicker lines to indicate their predominance in each condition (33). miRNA, microRNA; HK, Hexokinase; LDHA, lactate dehydrogenase A; HIF1, Hypoxia-inducible factor 1.

Figure 3

Overview of immunometabolism in tumor microenvironment.

Figure 4

miRNAs regulate glucose metabolism in tumor-associated macrophages. In TAMs, microRNAs influence glucose metabolism. Tumor cells’ respiration is less than their oxygen demand, culminating in hypoxia as well as HIF-1 overexpression. Extracellular vesicles (including miR-30c and miR-let-7a, among several others) are secreted into TAMs through hypoxia-induced cancer cells, suppressing the glycolysis-related metabolic pathway AKT/mTOR in TAMs. Decreased glucose metabolism then raises M2-type associated factors including TGF-β, COX-2, IL-6, and ARG-1, reduces M1-type related factors including TNF-α, IL-12, and IL-1β, resulting in M2-type macrophage rewiring and tumor growth and angiogenesis (215). TAM, Tumor-associated macrophages: HIF-1α, Hypoxia-inducible factor 1-alpha; mTOR, mammalian target of rapamycin; ARG-1, Arginase 1; IL, Interleukin; COX-2, cyclooxygenase 2; TGF-β, Transforming growth factor beta; TNF-α, Tumor necrosis factor alpha.