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The promise and peril of targeting cell metabolism for cancer therapy

  • Jonathan M. WeissEmail author
Focussed Research Review

Abstract

A major challenge of cancer immunotherapy is the potential for undesirable effects on bystander cells and tumor-associated immune cells. Fundamentally, we need to understand what effect targeting tumor metabolism has upon the metabolism and phenotype of tumor-associated leukocytes, whose function can be critical for effective cancer therapeutic strategies. Undesirable effects of cancer therapeutics are a major reason for drug-associated toxicity, which confounds drug dosing and efficacy. As with any chemotherapeutic agent, drugs targeting tumor metabolism will exert potent effects on host stromal cells and tumor-associated leukocytes. Any drug targeting glycolysis, for example, could metabolically starve tumor-infiltrating T cells, inhibit their effector function and enable tumor progression. The targeting of oxidative phosphorylation in tumors will have complex effects on the polarization and function of tumor-associated macrophages. In short, we need to improve our understanding of tumor and immune cell metabolism and devise ways to specifically target tumors without compromising necessary host metabolism. Exploiting cell-specific metabolic pathways to directly target tumor cells may minimize detrimental effects on tumor-associated leukocytes.

Keywords

Immunometabolism Tumor metabolism Itaconic acid Macrophages CITIM 2019 

List of abbreviations

2-DG

2-deoxy-D-glucose

ATP

Adenosine triphosphate

HIF-1α

Hypoxia-induced factor 1 alpha

IFNγ

Interferon gamma

Irg1

Immune-responsive gene 1

Keap1

Kelch like ECH associated protein 1

MAPK

Mitogen-activated protein kinase

MDSC

Myeloid-derived suppressor cell

NADPH

Nicotinamide adenine dinucleotide phosphate

Nrf2

Nuclear factor erythroid 2-related factor

OXPHOS

Oxidative phosphorylation

PDK

Pyruvate dehydrogenase kinase

ROS

Reactive oxygen species

SDH

Succinate dehydrogenase

TAM

Tumor associated macrophage

VEGF

Vascular endothelial growth factor

Notes

Funding

This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Cancer and Inflammation Program.

Compliance with ethical standards

Conflict of interest

The author declares that he has no conflict of interest.

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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply  2019

Authors and Affiliations

  1. 1.National Cancer InstituteFrederickUSA

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