Advances in Research on Cell Metabolic Interactions in the Tumor Microenvironment

WU Pengfei; YANG Zhi; LI Qingyan; WANG Denian

doi:10.12182/20240360606

Volume 55 Issue 2

Apr. 2024

Turn off MathJax

Article Contents

Abstract

References

JOURNAL OF SICHUAN UNIVERSITY (MEDICAL SCIENCES) > 2024 > 55(2): 482-489. > DOI: 10.12182/20240360606

WU Pengfei, YANG Zhi, LI Qingyan, et al. Advances in Research on Cell Metabolic Interactions in the Tumor Microenvironment[J]. Journal of Sichuan University (Medical Sciences), 2024, 55(2): 482-489. DOI: 10.12182/20240360606

Citation:

PDF (934 KB)

Advances in Research on Cell Metabolic Interactions in the Tumor Microenvironment

WU Pengfei^{1, 2,},
YANG Zhi³,
LI Qingyan¹,
WANG Denian^{1, 2, ,}

1.
Precision Medicine Research Center, Precision Medicine Key Laboratory of Sichuan Province, Institute of Respiratory and Comorbidity, West China Hospital, Sichuan University, Chengdu 610041, China
2.
Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Institute of Respiratory and Comorbidity, West China Hospital, Sichuan University, Chengdu 610041, China
3.
Department of Nephrology, West China Hospital, Sichuan University, Chengdu 610041, China

More Information

Corresponding author:
WANG Denian, Email: wangdenian623@163.com
Received Date: May 30, 2023
Revised Date: January 15, 2024
Published Date: March 19, 2024

Abstract

Abstract

Metabolic reprogramming plays a critical role in tumorigenesis and tumor progression. The metabolism and the proliferation of tumors are regulated by both intrinsic factors within the tumor and the availability of metabolites in the tumor microenvironment (TME). The metabolic niche within the TME is primarily orchestrated at 3 levels: 1) the regulation of tumor metabolism by factors intrinsic to the tumors, 2) the interaction between tumor cells and T cells, macrophages, and stromal cells, and 3) the metabolic heterogeneity of tumor cells within the tissue space. Herein, we provided a concise overview of the various metabolic regulatory modes observed in tumor cells. Additionally, we extensively analyzed the interaction between tumor cells and other cells within the TME, as well as the metabolic characteristics and functions of different types of cells. Ultimately, this review provides a theoretical basis and novel insights for the precision treatment of tumors.
- Metabolic reprogramming,
- Tumor microenvironment,
- Metabolic heterogeneity,
- Glycolysis,
- Metabolic therapy,
- Review

FullText(HTML)

References (73)

References

[1]	Vander HEIDEN M G, DeBERARDINIS R J. Understanding the intersections between metabolism and cancer biology. Cell,2017,168(4): 657–669. doi: 10.1016/j.cell.2016.12.039.
[2]	MARTÍNEZ-REYES I, CHANDEL N S. Cancer metabolism: looking forward. Nat Rev Cancer,2021,21(10): 669–680. doi: 10.1038/s41568-021-00378-6.
[3]	ELIA I, SCHMIEDER R, CHRISTEN S, et al. Organ-specific cancer metabolism and its potential for therapy. Handb Exp Pharmacol,2016,233: 321–353. doi: 10.1007/164_2015_10.
[4]	CHEN D, ZHANG X, LI Z, et al. Metabolic regulatory crosstalk between tumor microenvironment and tumor-associated macrophages. Theranostics,2021,11(3): 1016–1030. doi: 10.7150/thno.51777.
[5]	NAKAZAWA M S, KEITH B, SIMON M C. Oxygen availability and metabolic adaptations. Nat Rev Cancer,2016,16(10): 663–673. doi: 10.1038/nrc.2016.84.
[6]	VODNALA S K, EIL R, KISHTON R J, et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science,2019,363(6434): eaau0135. doi: 10.1126/science.aau0135.
[7]	KUMAR S, SHARIFE H, KREISEL T, et al. Intra-tumoral metabolic zonation and resultant phenotypic diversification are dictated by blood vessel proximity. Cell Metab,2019,30(1): 201–211.e6. doi: 10.1016/j.cmet.2019.04.003.
[8]	LYSSIOTIS C A, KIMMELMAN A C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol,2017,27(11): 863–875. doi: 10.1016/j.tcb.2017.06.003.
[9]	WARBURG O, WIND F, NEGELEIN E. The metabolism of tumors in the body. J Gen Physiol,1927,8(6): 519–530. doi: 10.1085/jgp.8.6.519.
[10]	WITNEY T H, JAMES M L, SHEN B, et al. PET imaging of tumor glycolysis downstream of hexokinase through noninvasive measurement of pyruvate kinase M2. Sci Transl Med,2015,7(310): 310ra169. doi: 10.1126/scitranslmed.aac6117.
[11]	HSU P P, SABATINI D M. Cancer cell metabolism: Warburg and beyond. Cell,2008,134(5): 703–707. doi: 10.1016/j.cell.2008.08.021.
[12]	REID M A, ALLEN A E, LIU S, et al. Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism. Nat Commun,2018,9(1): 5442. doi: 10.1038/s41467-018-07868-6.
[13]	DEBERARDINIS R J, MANCUSO A, DAIKHIN E, et al. Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A,2007,104(49): 19345–19350. doi: 10.1073/pnas.0709747104.
[14]	ROY D G, CHEN J, MAMANE V, et al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab,2020,31(2): 250–266.e9. doi: 10.1016/j.cmet.2020.01.006.
[15]	MELLOR A L, MUNN D H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol,2004,4(10): 762–774. doi: 10.1038/nri1457.
[16]	SPINELLI J B, YOON H, RINGEL A E, et al. Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass. Science,2017,358(6365): 941–946. doi: 10.1126/science.aam9305.
[17]	CSIBI A, FENDT S M, LI C, et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell,2013,153(4): 840–854. doi: 10.1016/j.cell.2013.04.023.
[18]	BIRSOY K, WANG T, CHEN W W, et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell,2015,162(3): 540–551. doi: 10.1016/j.cell.2015.07.016.
[19]	MUKHA D, FOKRA M, FELDMAN A, et al. Glycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth. Cell Metab,2022,34(5): 775–782.e9. doi: 10.1016/j.cmet.2022.04.006.
[20]	WANG H C, HUO Y N, LEE W S. Folic acid prevents the progesterone-promoted proliferation and migration in breast cancer cell lines. Eur J Nutr,2020,59(6): 2333–2344. doi: 10.1007/s00394-019-02077-3.
[21]	GHERGUROVICH J M, XU X, WANG J Z, et al. Methionine synthase supports tumour tetrahydrofolate pools. Nat Metab,2021,3(11): 1512–1520. doi: 10.1038/s42255-021-00465-w.
[22]	SHANG M, YANG H, YANG R, et al. The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation. Nat Commun,2021,12(1): 1940. doi: 10.1038/s41467-021-22173-5.
[23]	GEERAERTS X, BOLLI E, FENDT S M, et al. Macrophage metabolism as therapeutic target for cancer, atherosclerosis, and obesity. Front Immunol,2017,8: 289. doi: 10.3389/fimmu.
[24]	CHEN D S, MELLMAN I. Oncology meets immunology: the cancer-immunity cycle. Immunity,2013,39(1): 1–10. doi: 10.1016/j.immuni.2013.07.012.
[25]	REINA-CAMPOS M, SCHARPING N E, GOLDRATH A W. CD8⁺ T cell metabolism in infection and cancer. Nat Rev Immunol,2021,21(11): 718–738. doi: 10.1038/s41577-021-00537-8.
[26]	CASCONE T, MCKENZIE J A, MBOFUNG R M, et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab,2018,27(5): 977–987.e4. doi: 10.1016/j.cmet.2018.02.024.
[27]	CHANG C H, CURTIS J D, MAGGI L B, Jr, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell,2013,153(6): 1239–1251. doi: 10.1016/j.cell.2013.05.016.
[28]	PENG M, YIN N, CHHANGAWALA S, et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science,2016,354(6311): 481–484. doi: 10.1126/science.aaf6284.
[29]	CHAM C M, GAJEWSKI T F. Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8⁺ effector T cells. J Immunol,2005,174(8): 4670–4677. doi: 10.4049/jimmunol.174.8.4670.
[30]	CHAM C M, DRIESSENS G, O'KEEFE J P, et al. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8⁺ T cells. Eur J Immunol,2008,38(9): 2438–2450. doi: 10.1002/eji.200838289.
[31]	BRAND A, SINGER K, KOEHL G E, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab,2016,24(5): 657–671. doi: 10.1016/j.cmet.2016.08.011.
[32]	ZHANG Y, KURUPATI R, LIU L, et al. Enhancing CD8⁺ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell,2017,32(3): 377–391.e9. doi: 10.1016/j.ccell.2017.08.004.
[33]	QIU J, VILLA M, SANIN D E, et al. Acetate promotes T cell effector function during glucose restriction. Cell Rep,2019,27(7): 2063–2074.e5. doi: 10.1016/j.celrep.2019.04.022.
[34]	VETTORE L, WESTBROOK R L, TENNANT D A. New aspects of amino acid metabolism in cancer. Br J Cancer,2020,122(2): 150–156. doi: 10.1038/s41416-019-0620-5.
[35]	WANG R, DILLON C P, SHI L Z, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity,2011,35(6): 871–882. doi: 10.1016/j.immuni.2011.09.021.
[36]	CARR E L, KELMAN A, WU G S, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol,2010,185(2): 1037–1044. doi: 10.4049/jimmunol.0903586.
[37]	JOHNSON M O, WOLF M M, MADDEN M Z, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell,2018,175(7): 1780–1795.e19. doi: 10.1016/j.cell.2018.10.001.
[38]	BRODY J R, COSTANTINO C L, BERGER A C, et al. Expression of indoleamine 2,3-dioxygenase in metastatic malignant melanoma recruits regulatory T cells to avoid immune detection and affects survival. Cell Cycle,2009,8(12): 1930–1934. doi: 10.4161/cc.8.12.8745.
[39]	MEZRICH J D, FECHNER J H, ZHANG X, et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol,2010,185(6): 3190–3198. doi: 10.4049/jimmunol.0903670.
[40]	GEIGER R, RIECKMANN J C, WOLF T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell,2016,167(3): 829–842.e13. doi: 10.1016/j.cell.2016.09.031.
[41]	SINCLAIR L V, ROLF J, EMSLIE E, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol,2013,14(5): 500–508. doi: 10.1038/ni.2556.
[42]	CASSETTA L, POLLARD J W. Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discov,2018,17(12): 887–904. doi: 10.1038/nrd.2018.169.
[43]	BLAGIH J, ZANI F, CHAKRAVARTY P, et al. Cancer-specific loss of p53 leads to a modulation of myeloid and T cell responses. Cell Rep,2020,30(2): 481–496.e6. doi: 10.1016/j.celrep.2019.12.028.
[44]	LUJAMBIO A, AKKARI L, SIMON J, et al. Non-cell-autonomous tumor suppression by p53. Cell,2013,153(2): 449–460. doi: 10.1016/j.cell.2013.03.020.
[45]	MILLER A, NAGY C, KNAPP B, et al. Exploring metabolic configurations of single cells within complex tissue microenvironments. Cell Metab,2017,26(5): 788–800.e6. doi: 10.1016/j.cmet.2017.08.014.
[46]	PENNY H L, SIEOW J L, ADRIANI G, et al. Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma. Oncoimmunology,2016,5(8): e1191731. doi: 10.1080/2162402X.2016.1191731.
[47]	COLEGIO O R, CHU N Q, SZABO A L, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature,2014,513(7519): 559–563. doi: 10.1038/nature13490.
[48]	ZHANG D, TANG Z, HUANG H, et al. Metabolic regulation of gene expression by histone lactylation. Nature,2019,574(7779): 575–580. doi: 10.1038/s41586-019-1678-1.
[49]	LIU P S, WANG H, LI X, et al. alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol,2017,18(9): 985–994. doi: 10.1038/ni.3796.
[50]	PALMIERI E M, MENGA A, MARTIN-PEREZ R, et al. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep,2017,20(7): 1654–1666. doi: 10.1016/j.celrep.2017.07.054.
[51]	LECA J, MARTINEZ S, LAC S, et al. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J Clin Invest,2016,126(11): 4140–4156. doi: 10.1172/JCI87734.
[52]	PAVLIDES S, WHITAKER-MENEZES D, CASTELLO-CROS R, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle,2009,8(23): 3984–4001. doi: 10.4161/cc.8.23.10238.
[53]	YANG L, ACHREJA A, YEUNG T L, et al. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab,2016,24(5): 685–700. doi: 10.1016/j.cmet.2016.10.011.
[54]	SOUSA C M, BIANCUR D E, WANG X, et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature,2016,536(7617): 479–483. doi: 10.1038/nature19084.
[55]	AUCIELLO F R, BULUSU V, OON C, et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov,2019,9(5): 617–627. doi: 10.1158/2159-8290.CD-18-1212.
[56]	BERTERO T, OLDHAM W M, GRASSET E M, et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab,2019,29(1): 124–140.e10. doi: 10.1016/j.cmet.2018.09.012.
[57]	SALIMIAN RIZI B, CANEBA C, NOWICKA A, et al. Nitric oxide mediates metabolic coupling of omentum-derived adipose stroma to ovarian and endometrial cancer cells. Cancer Res,2015,75(2): 456–471. doi: 10.1158/0008-5472.CAN-14-1337.
[58]	WANG W, KRYCZEK I, DOSTAL L, et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell,2016,165(5): 1092–1105. doi: 10.1016/j.cell.2016.04.009.
[59]	XIAO Z, DAI Z, LOCASALE J W. Metabolic landscape of the tumor microenvironment at single cell resolution. Nat Commun,2019,10(1): 3763. doi: 10.1038/s41467-019-11738-0.
[60]	HENSLEY C T, FAUBERT B, YUAN Q, et al. Metabolic heterogeneity in human lung tumors. Cell,2016,164(4): 681–694. doi: 10.1016/j.cell.2015.12.034.
[61]	PAN M, REID M A, LOWMAN X H, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol,2016,18(10): 1090–1101. doi: 10.1038/ncb3410.
[62]	OKEGAWA T, MORIMOTO M, NISHIZAWA S, et al. Intratumor heterogeneity in primary kidney cancer revealed by metabolic profiling of multiple spatially separated samples within tumors. EBioMedicine,2017,19: 31–38. doi: 10.1016/j.ebiom.2017.04.009.
[63]	FARBER S, DIAMOND L K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med,1948,238(23): 787–793. doi: 10.1056/NEJM194806032382301.
[64]	PALSSON-MCDERMOTT E M, DYCK L, ZASLONA Z, et al. Pyruvate kinase M2 is required for the expression of the immune checkpoint PD-L1 in immune cells and tumors. Front Immunol,2017,8: 1300. doi: 10.3389/fimmu.2017.01300.
[65]	KUNG C, HIXON J, CHOE S, et al. Small molecule activation of PKM2 in cancer cells induces serine auxotrophy. Chem Biol,2012,19(9): 1187–1198. doi: 10.1016/j.chembiol.2012.07.021.
[66]	LADANYI A, MUKHERJEE A, KENNY H A, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene,2018,37(17): 2285–2301. doi: 10.1038/s41388-017-0093-z.
[67]	HUANG S C, EVERTS B, IVANOVA Y, et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol,2014,15(9): 846–855. doi: 10.1038/ni.2956.
[68]	RENNER K, SINGER K, KOEHL G E, et al. Metabolic hallmarks of tumor and immune cells in the tumor microenvironment. Front Immunol,2017,8: 248. doi: 10.3389/fimmu.2017.00248.
[69]	RON-HAREL N, SANTOS D, GHERGUROVICH J M, et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab,2016,24(1): 104–117. doi: 10.1016/j.cmet.2016.06.007.
[70]	SULLIVAN M R, DARNELL A M, REILLY M F, et al. Methionine synthase is essential for cancer cell proliferation in physiological folate environments. Nat Metab,2021,3(11): 1500–1511. doi: 10.1038/s42255-021-00486-5.
[71]	BATTAGLIA M, STABILINI A, RONCAROLO M G. Rapamycin selectively expands CD4⁺CD25⁺FoxP3⁺ regulatory T cells. Blood,2005,105(12): 4743–4748. doi: 10.1182/blood-2004-10-3932.
[72]	SCHURICH A, MAGALHAES I, MATTSSON J. Metabolic regulation of CAR T cell function by the hypoxic microenvironment in solid tumors. Immunotherapy,2019,11(4): 335–345. doi: 10.2217/imt-2018-0141.
[73]	JASPERS J E, BRENTJENS R J. Development of CAR T cells designed to improve antitumor efficacy and safety. Pharmacol Ther,2017,178: 83–91. doi: 10.1016/j.pharmthera.2017.03.012.

OPEN ACCESS This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International license (CC BY-NC 4.0). In other words, the full-text content of the journal is made freely available for third-party users to copy and redistribute in any medium or format, and to remix, transform, and build upon the content of the journal. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may not use the content of the journal for commercial purposes. For more information about the license, visit https://creativecommons.org/licenses/by-nc/4.0

Relative Articles

Supplements (0)

Cited By