The cellular metabolic landscape in the tumor milieu regulates the activity of myeloid infiltrates

Abstract

Malignant cells upregulate distinct energy metabolism programs that support their proliferation, migration, and adaptation to the stressful tumor microenvironment (TME). Additionally, this exaggerated metabolic activity allows cancer cells to hijack essential nutrients and outcompete neighboring infiltrating immune cells, thereby impairing antitumor immunity. During recent years, there has been great interest in the field to understand the tumor-induced energy metabolism signals that regulate the function of immune cells in individuals with cancer. Accordingly, it is now well accepted that uncovering the mechanisms that instruct the metabolic behavior of cancer cells and tumor-associated immune cells is an indispensable strategy for the development of new approaches to overcome immune suppression in tumors. Thus, in this minireview, we briefly discuss the interaction between particular metabolic signaling pathways and immunosuppressive activity in different subsets of myeloid cells within the TME. Additionally, we illustrate potential central mechanisms controlling the metabolic reprogramming of myeloid cells in response to tumor-derived factors.

Keywords: Tumor microenvironment; immune suppression; metabolic reprogramming; myeloid cells.

Fig. 1. STAT3/STAT5 and AMPK mediate the metabolic reprogramming of MDSCs to FAO within the TME.

AMPK induces PGC1β/PPARγ to upregulate CPT1 (1). AMPK phosphorylates ULK1, which promotes mitophagy and enhances mitochondrial function (2). Additionally, AMPK induces PGC1α to block mtROS, which can shift MDSCs to glycolysis driven by HIF-1α (3). In addition, tumor-derived GM-CSF and G-CSF induce STAT3/STAT5 signaling, leading to an increase in lipid uptake through the translocase CD36, which activates oxidative metabolism and promotes the suppressive functions of MDSCs (4). Whether these signaling events occur simultaneously or are partitioned and occur in a particular order remains to be determined

Fig. 2. Malignant cells are characterized by metabolic alterations that correspond to their pathological proliferation, differentiation, and metastasis.

The high consumption rate of glucose, lipids, and amino acids, which is associated with a massive release of metabolites and waste by-products, shapes the metabolic landscape of myeloid cells within the TME. Ultimately, this shaping leads to the expansion of suppressive myeloid cells, which are incapable of presenting antigens and priming effective T-cell responses against tumors