Metabolic Signaling in the Tumor Microenvironment

Abstract

Cancer cells must reprogram their metabolism to sustain rapid growth. This is accomplished in part by switching to aerobic glycolysis, uncoupling glucose from mitochondrial metabolism, and performing anaplerosis via alternative carbon sources to replenish intermediates of the tricarboxylic acid (TCA) cycle and sustain oxidative phosphorylation (OXPHOS). While this metabolic program produces adequate biosynthetic intermediates, reducing agents, ATP, and epigenetic remodeling cofactors necessary to sustain growth, it also produces large amounts of byproducts that can generate a hostile tumor microenvironment (TME) characterized by low pH, redox stress, and poor oxygenation. In recent years, the focus of cancer metabolic research has shifted from the regulation and utilization of cancer cell-intrinsic pathways to studying how the metabolic landscape of the tumor affects the anti-tumor immune response. Recent discoveries point to the role that secreted metabolites within the TME play in crosstalk between tumor cell types to promote tumorigenesis and hinder the anti-tumor immune response. In this review, we will explore how crosstalk between metabolites of cancer cells, immune cells, and stromal cells drives tumorigenesis and what effects the competition for resources and metabolic crosstalk has on immune cell function.

Keywords: cancer metabolism; immune response; oncometabolite; tumor microenvironment.

Figure 1

Lactate signaling in the TME: Lactate is produced in large quantities by cancer cells and CAFs and secreted into the TME. This lactate activates signaling pathways in several cell types, such as stabilizing HIF expression in the cancer cell and TAM, altering TAM gene expression to reinforce M2 polarization, triggering TAM VEGF production to promote vascularization, and inhibiting NFAT-dependent effector functions in T and NK cells. High lactate also contributes to tumor progression by directly killing anti-tumor immune cells.