Lactate supports a metabolic-epigenetic link in macrophage polarization

Jordan T. Noe, Beatriz E. Rendon, Anne E. Geller, Lindsey R. Conroy, Samantha M. Morrissey, Lyndsay E.A. Young, Ronald C. Bruntz, Eun J. Kim, Ashley Wise-Mitchell, Mariana Barbosa De Souza Rizzo, Eric R. Relich, Becca V. Baby, Lance A. Johnson, Hayley C. Affronti, Kelly M. McMasters, Brian F. Clem, Matthew S. Gentry, Jun Yan, Kathryn E. Wellen, Ramon C. SunRobert A. Mitchell

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)-induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate- citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage-dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)-driven metabolic-epigenetic link in M2 macrophages.

Original languageEnglish
Article numbereabi8602
JournalScience advances
Issue number46
StatePublished - Nov 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Predoctoral Fellowship Award F30CA232550 (to J.T.N.), NIH Pre- to Postdoctoral Transition Award 4K00CA212455 (to H.C.A.), NIH Research Grant R35NS116824 (to M.S.G.), NIH Research Grant R01AG060056 (to L.A.J.), NIH Research Grant R01AG062550 (to L.A.J.), NIH Research Grant R01CA213990 (to J.Y.), NIH Research Grant R01DK116005 (to K.E.W.), NIH Research Grant R01CA174761 (to K.E.W.), NIH Research Grant R01AG066653 (to R.C.S.), V Scholar Grant (to R.C.S.), NIH Research Grant R01CA186661 (to R.A.M.), NIH Research Grant GB130096P3 (to R.A.M.), and NIH Project Grant P20GM135004 (to J.Y. and R.A.M.).

Publisher Copyright:
Copyright © 2021 The Authors.

ASJC Scopus subject areas

  • General


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