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The promise and peril of targeting cell metabolism for cancer therapy

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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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

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Funding

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

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  1. National Cancer Institute, 1050 Boyles Street, Frederick, MD, 21702, USA

    Jonathan M. Weiss

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This paper is a Focussed Research Review based on a presentation given at the Sixth International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM 2019), held in Tbilisi, Georgia, 29th April–2nd May 2019. It is part of a series of CITIM 2019 papers in Cancer Immunology, Immunotherapy.

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Weiss, J.M. The promise and peril of targeting cell metabolism for cancer therapy. Cancer Immunol Immunother 69, 255–261 (2020). https://doi.org/10.1007/s00262-019-02432-7

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