Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

Abstract

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

Keywords: NK cells; T cells; cancer; immune cells; immunometabolism; immunosuppression; macrophages; metabolites.

Figure 1

Metabolic differences between normal cells (A) and cancer cells (B). Normal/quiescent cells in aerobiosis metabolize glucose mainly to pyruvate, which is then oxidized in the mitochondria to CO₂ using the TCA cycle and OxPhos for the generation of ATP. ATP synthesis takes places preferentially in the mitochondria. In anaerobiosis, pyruvate is metabolized to lactate instead. Cancer cells in aerobiosis or anaerobiosis convert most glucose to lactate (which is exported to the TME), while diverting some glycolytic intermediates to the PPP, which generates NADPH and pentoses for the synthesis of nucleic acids. ATP synthesis is largely cytosolic. Glutaminolysis generates glutamate, which is converted to α-ketoglutarate, a major substrate to refuel the TCA cycle. The TCA cycle intermediate citrate is exported to the cytosol, where it is converted to acetyl-CoA, used for the synthesis of lipids.

Figure 2

Overview of metabolic changes in some immune cell types upon activation. Macrophages, CD4⁺ T cells and NK cells are shown. Resting or naïve cells typically display a low metabolic rate (low glycolysis, low OxPhos). M0 macrophages differentiate into M1 and M2 macrophages, naïve CD4+ T cells differentiate into Teffs or Tregs, and resting NK cells become activated. Each cell subtype displays different metabolic requirements and repertoire of cytokines to function.

Figure 3

Characteristics of the TME. Tumor cells (and other cells in the tumor) deplete nutrient levels (glucose, glutamine, amino acids, O₂, etc.) in the TME, increase the levels of some metabolites, such as lactic acid or L-kynurenine, and secrete cytokines (including TGF-β and IL-10), which inhibit the metabolism, effector function and proliferation in immune cell, and may cause apoptosis.