Metabolic interventions in the immune response to cancer

Abstract

At the centre of the therapeutic dilemma posed by cancer is the question of how to develop more effective treatments that discriminate between normal and cancerous tissues. Decades of research have shown us that universally applicable principles are rare, but two well-accepted concepts have emerged: first, that malignant transformation goes hand in hand with distinct changes in cellular metabolism; second, that the immune system is critical for tumour control and clearance. Unifying our understanding of tumour metabolism with immune cell function may prove to be a powerful approach in the development of more effective cancer therapies. Here, we explore how nutrient availability in the tumour microenvironment shapes immune responses and identify areas of intervention to modulate the metabolic constraints placed on immune cells in this setting.

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Fig. 1: Metabolic requirements for anticancer immunity.
Fig. 2: The TME supports the metabolism of tumour-facilitating cells.
Fig. 3: Attractive metabolic targets for combination therapies.
Fig. 4: Metabolically tuning chimeric antigen receptor T cell therapy.

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Acknowledgements

The authors thank M. D. Buck and members of the Pearce laboratories for discussion and critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (NIH) (AI110481 to E.J.P.; AI091965 and CA158823 to E.L.P.) and the Max Planck Society.

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Nature Reviews Immunology thanks M. Haigis and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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All the authors contributed to the discussion of content and to the writing, review and editing of the manuscript. D.O. and D.E.S. were involved in researching data for the article.

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Correspondence to Edward J. Pearce or Erika L. Pearce.

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E.L.P. is a scientific advisory board member of Immunomet and a founder of Rheos Medicines. E.J.P. is a founder of Rheos Medicines.

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Glossary

Warburg metabolism

Diversion of glucose metabolism towards lactate production in the presence of oxygen.

Oxidative phosphorylation

(OXPHOS). An electron transport chain-mediated process in which the energy resulting from the oxidation of carbon compounds is used to produce ATP.

Electron transport chain

Protein complexes spanning the inner mitochondrial membrane, which couple redox reactions to the establishment of a proton gradient used to generate ATP.

Pentose phosphate pathway

A metabolic pathway that generates NADPH and intermediates for nucleotide synthesis.

Leukapheresis

A laboratory procedure to extract the cellular component from blood.

Phosphoproteome

A subset of the proteins in a cell that either contain a phosphate group or can be phosphorylated.

Metformin

A type of biguanide that can induce AMPK activity and can disrupt the electron transport chain by reducing the activity of complex I.

Biguanides

A class of compounds that are used for the treatment of type 2 diabetes, as they regulate glucose metabolism.

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O’Sullivan, D., Sanin, D.E., Pearce, E.J. et al. Metabolic interventions in the immune response to cancer. Nat Rev Immunol 19, 324–335 (2019). https://doi.org/10.1038/s41577-019-0140-9

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