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Cancer cell metabolism and antitumour immunity

Nature Reviews Immunology (2024)Cite this article

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Abstract

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

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Fig. 1: Effects of glucose, lactate and the TCA cycle on anticancer immunity.
Fig. 2: Effects of fatty acid and eicosanoid metabolism on anticancer immunity.
Fig. 3: Effects of nucleotide and amino acid metabolism on anticancer immunity.

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Acknowledgements

M.D.M. is supported by the Future Leaders 2023 Postdoctoral Fellowship from the Brain Tumour Charity (#BTC224874-01). J.C.R. receives support related to this work from an R01 grant from the National Institutes of Health National Cancer Institute (NIH/NCI) (#CA217987). Among other funds, L.G. is/has been supported by an R01 grant from the NIH/NCI (#CA271915) and two Breakthrough Level 2 grants from the US Department of Defense (DoD) Breast Cancer Research Program (BCRP) (#BC180476P1, #BC210945). Among other funds, C.V.-B. is supported by an R01 grant from the NHI National Institute of Neurological Disorders and Stroke (NIH/NINDS) (#NS131945-01) and an R21 grant from the NIH/NCI (#CA280787-01).

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Authors and Affiliations

  1. Department of Radiation Oncology, Weill Cornell Medicine, New York, NY, USA

    Mara De Martino, Lorenzo Galluzzi & Claire Vanpouille-Box

  2. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA

    Jeffrey C. Rathmell

  3. Sandra and Edward Meyer Cancer Center, New York, NY, USA

    Lorenzo Galluzzi & Claire Vanpouille-Box

  4. Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA

    Lorenzo Galluzzi

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C.V.-B. and L.G. conceived the article. M.D.M., C.V.-B. and L.G. wrote the first version of the manuscript with constructive input from J.C.R. M.D.M. prepared display items under supervision from C.V.-B. and L.G. All authors approved the submitted version of the article.

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Correspondence to Lorenzo Galluzzi or Claire Vanpouille-Box.

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Competing interests

J.C.R. is a founder and scientific advisory board member of Sitryx Therapeutics. L.G. is/has been holding research contracts with Lytix Biopharma, Promontory and Onxeo; has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. The other authors declare no competing interests.

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Supplementary information

Glossary

Anabolism

A set of metabolic pathways that build large molecules from smaller units in support of cell growth and proliferation.

Autophagy

A lysosome-dependent catabolic pathway that ensures the degradation of supernumerary, dysfunctional or potentially cytotoxic cytoplasmic material.

Cancer-associated fibroblasts

(CAFs). A heterogeneous population of fibroblasts that define the tumour stroma and communicate with both malignant and immune components of the tumour microenvironment.

Catabolism

A set of metabolic pathways that break down large molecules into smaller units for recycling or for the production of ATP.

Crotonylation

The post-translational modification of lysine residues by crotonyl-CoA.

De novo lipid biosynthesis

A metabolic cascade converting acetyl-CoA into long-chain lipids for cellular anabolism.

Immune checkpoint inhibitors

(ICIs). Monoclonal antibodies targeting co-inhibitory T cell receptors in support of restored anticancer immunosurveillance.

Lactylation

The post-translational modification of lysine residues by lactate.

Myeloid-derived suppressor cells

(MDSCs). Poorly differentiated myeloid cells with prominent immunosuppressive and tumour-promoting properties.

Oxidative phosphorylation

(OXPHOS). A mitochondrial pathway, fed by NADH and succinate provided by the tricarboxylic acid cycle (TCA cycle), that generates ATP from a series of oxidation reactions that culminate with the generation of H2O.

Pentose phosphate pathway

A metabolic shunt that diverts glycolytic intermediates towards the synthesis of nucleotides, some amino acids and antioxidants.

T cell exhaustion

A state of T cell dysfunction that arises during many chronic infections and cancer.

Tricarboxylic acid cycle

(TCA cycle). A mitochondrial circuit that ensures adequate levels of key metabolites involved in several catabolic and anabolic reactions, including acetyl-CoA, pyruvate, oxaloacetate, succinate and α-ketoglutarate.

Tumour-associated macrophages

(TAMs). A heterogeneous and plastic population of intratumoural macrophages with a spectrum of activity ranging from prominently antitumour (so-called M1-like TAMs) to prominently pro-tumour (so-called M2-like TAMs). Caution should be made when extrapolating these in vitro-defined M1 and M2 phenotypes to in vivo settings.

Urea cycle

A metabolic pathway to convert excess ammonia into urea for excretion.

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De Martino, M., Rathmell, J.C., Galluzzi, L. et al. Cancer cell metabolism and antitumour immunity. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-01026-4

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