Metabolic reprogramming in the tumor microenvironment of liver cancer

1.

Satriano L, Lewinska M, Rodrigues PM, Banales JM, Andersen JB. Metabolic rearrangements in primary liver cancers: cause and consequences. Nat Rev Gastroenterol Hepatol. 2019;16:748–66. https://doi.org/10.1038/s41575-019-0217-8.CrossRefPubMed

2.

Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345–62. https://doi.org/10.1016/S0140-6736(22)01200-4.CrossRefPubMed

3.

Oh D-Y, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evidence. 2022;1:EVIDoa2200015. https://doi.org/10.1056/EVIDoa2200015.CrossRef

4.

Kelley RK, et al. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401:1853–65. https://doi.org/10.1016/S0140-6736(23)00727-4.CrossRefPubMed

5.

Schwabe RF, Greten TF. Gut microbiome in HCC: mechanisms, diagnosis and therapy. J Hepatol. 2020;72:230–8. https://doi.org/10.1016/j.jhep.2019.08.016.CrossRefPubMed

6.

Hung MH, et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun. 2021;12:1455. https://doi.org/10.1038/s41467-021-21804-1.CrossRefPubMedPubMedCentral

7.

Miallot R, Galland F, Millet V, Blay JY, Naquet P. Metabolic landscapes in sarcomas. J Hematol Oncol. 2021;14:114. https://doi.org/10.1186/s13045-021-01125-y.CrossRefPubMedPubMedCentral

8.

Schmidt DR, et al. Metabolomics in cancer research and emerging applications in clinical oncology. CA Cancer J Clin. 2021;71:333–58. https://doi.org/10.3322/caac.21670.CrossRefPubMedPubMedCentral

9.

Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33. https://doi.org/10.1126/science.1160809.CrossRefPubMedPubMedCentral

10.

Xia L, et al. The cancer metabolic reprogramming and immune response. Mol Cancer. 2021;20:28. https://doi.org/10.1186/s12943-021-01316-8.CrossRefPubMedPubMedCentral

11.

Sonveaux P, et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest. 2008;118:3930–42. https://doi.org/10.1172/JCI36843.CrossRefPubMedPubMedCentral

12.

Pavlides S, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009;8:3984–4001. https://doi.org/10.4161/cc.8.23.10238.CrossRefPubMed

13.

Locasale JW, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43:869–74. https://doi.org/10.1038/ng.890.CrossRefPubMedPubMedCentral

14.

Schwenck J, et al. Advances in PET imaging of cancer. Nat Rev Cancer. 2023;23:474–90. https://doi.org/10.1038/s41568-023-00576-4.CrossRefPubMed

15.

Boroughs LK, DeBerardinis RJ. Metabolic pathways promoting cancer cell survival and growth. Nat Cell Biol. 2015;17:351–9. https://doi.org/10.1038/ncb3124.CrossRefPubMedPubMedCentral

16.

Chang CH, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015;162:1229–41. https://doi.org/10.1016/j.cell.2015.08.016.CrossRefPubMedPubMedCentral

17.

Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest. 2007;117:1147–54. https://doi.org/10.1172/JCI31178.CrossRefPubMedPubMedCentral

18.

Leone RD, Powell JD. Metabolism of immune cells in cancer. Nat Rev Cancer. 2020;20:516–31. https://doi.org/10.1038/s41568-020-0273-y.CrossRefPubMedPubMedCentral

19.

Li X, et al. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019;16:425–41. https://doi.org/10.1038/s41571-019-0203-7.CrossRefPubMed

20.

Wang T, et al. Inosine is an alternative carbon source for CD8(+)-T-cell function under glucose restriction. Nat Metab. 2020;2:635–47. https://doi.org/10.1038/s42255-020-0219-4.CrossRefPubMedPubMedCentral

21.

Liu L, et al. Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1alpha-dependent. Proc Natl Acad Sci U S A. 2016;113:1564–9. https://doi.org/10.1073/pnas.1518000113.CrossRefPubMedPubMedCentral

22.

Miller A, et al. Exploring metabolic configurations of single cells within complex tissue microenvironments. Cell Metab. 2017;26:788–800. https://doi.org/10.1016/j.cmet.2017.08.014.CrossRefPubMed

23.

Hepatocellular carcinoma. Nat Rev Dis Primers 7, 7, https://doi.org/10.1038/s41572-021-00245-6 (2021).

24.

Bidkhori G, et al. Metabolic network-based stratification of hepatocellular carcinoma reveals three distinct tumor subtypes. Proc Natl Acad Sci U S A. 2018;115:E11874–83. https://doi.org/10.1073/pnas.1807305115.CrossRefPubMedPubMedCentral

25.

Calderaro J, Ziol M, Paradis V, Zucman-Rossi J. Molecular and histological correlations in liver cancer. J Hepatol. 2019;71:616–30. https://doi.org/10.1016/j.jhep.2019.06.001.CrossRefPubMed

26.

Xing X, et al. Integrated omics landscape of hepatocellular carcinoma suggests proteomic subtypes for precision therapy. Cell Rep Med. 2023;4: 101315. https://doi.org/10.1016/j.xcrm.2023.101315.CrossRefPubMedPubMedCentral

27.

Deng M, et al. Proteogenomic characterization of cholangiocarcinoma. Hepatology. 2023;77:411–29. https://doi.org/10.1002/hep.32624.CrossRefPubMed

28.

Murai H, et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology. 2023;77:77–91. https://doi.org/10.1002/hep.32573.CrossRefPubMed

29.

Dong L, et al. Proteogenomic characterization identifies clinically relevant subgroups of intrahepatic cholangiocarcinoma. Cancer Cell. 2022;40:70–87. https://doi.org/10.1016/j.ccell.2021.12.006.CrossRefPubMed

30.

Gao Q, et al. Integrated proteogenomic characterization of HBV-related hepatocellular carcinoma. Cell. 2019;179:561–77. https://doi.org/10.1016/j.cell.2019.08.052.CrossRefPubMed

31.

Nwosu ZC, et al. Identification of the consistently altered metabolic targets in human hepatocellular carcinoma. Cell Mol Gastroenterol Hepatol. 2017;4:303–23. https://doi.org/10.1016/j.jcmgh.2017.05.004.CrossRefPubMedPubMedCentral

32.

Ji S, et al. Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology. Sci Transl Med. 2023;15:eadg3358. https://doi.org/10.1126/scitranslmed.adg3358.CrossRefPubMed

33.

Yang HC, Stern A, Chiu DT. G6PD: a hub for metabolic reprogramming and redox signaling in cancer. Biomed J. 2021;44:285–92. https://doi.org/10.1016/j.bj.2020.08.001.CrossRefPubMed

34.

Hong X, et al. PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis. Gut. 2014;63:1635–47. https://doi.org/10.1136/gutjnl-2013-305302.CrossRefPubMed

35.

Gao LP, et al. Ineffective GSH regeneration enhances G6PD-knockdown Hep G2 cell sensitivity to diamide-induced oxidative damage. Free Radic Biol Med. 2009;47:529–35. https://doi.org/10.1016/j.freeradbiomed.2009.05.029.CrossRefPubMed

36.

Li B, et al. Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma. Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000553.CrossRefPubMed

37.

Huang Q, et al. Metabolic characterization of hepatocellular carcinoma using nontargeted tissue metabolomics. Cancer Res. 2013;73:4992–5002. https://doi.org/10.1158/0008-5472.CAN-13-0308.CrossRefPubMed

38.

Yang F, et al. Metabolic reprogramming and its clinical implication for liver cancer. Hepatology. 2023;78:1602–24. https://doi.org/10.1097/HEP.0000000000000005.CrossRefPubMed

39.

Yang Z, et al. Lactylome analysis suggests lactylation-dependent mechanisms of metabolic adaptation in hepatocellular carcinoma. Nat Metab. 2023;5:61–79. https://doi.org/10.1038/s42255-022-00710-w.CrossRefPubMed

40.

Wang ZX, et al. Preoperative serum liver enzyme markers for predicting early recurrence after curative resection of hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2015;14:178–85. https://doi.org/10.1016/s1499-3872(15)60353-8.CrossRefPubMed

41.

Faloppi L, et al. The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management. BMC Cancer. 2014;14:110. https://doi.org/10.1186/1471-2407-14-110.CrossRefPubMedPubMedCentral

42.

Faloppi L, et al. The correlation between LDH serum levels and clinical outcome in advanced biliary tract cancer patients treated with first line chemotherapy. Sci Rep. 2016;6:24136. https://doi.org/10.1038/srep24136.CrossRefPubMedPubMedCentral

43.

Zhang MS, et al. Hypoxia-induced macropinocytosis represents a metabolic route for liver cancer. Nat Commun. 2022;13:954. https://doi.org/10.1038/s41467-022-28618-9.CrossRefPubMedPubMedCentral

44.

Lu M, et al. Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition. Acta Biochim Biophys Sin (Shanghai). 2018;50:370–80. https://doi.org/10.1093/abbs/gmy009.CrossRefPubMed

45.

Kowalik MA, et al. Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis. Oncotarget. 2016;7:32375–93. https://doi.org/10.18632/oncotarget.8632.CrossRefPubMedPubMedCentral

46.

Zhu Q, et al. O-GlcNAcylation plays a role in tumor recurrence of hepatocellular carcinoma following liver transplantation. Med Oncol. 2012;29:985–93. https://doi.org/10.1007/s12032-011-9912-1.CrossRefPubMed

47.

Phoomak C, et al. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation. Sci Rep. 2017;7:43842. https://doi.org/10.1038/srep43842.CrossRefPubMedPubMedCentral

48.

Lin M, et al. Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma. Onco Targets Ther. 2018;11:3101–10. https://doi.org/10.2147/OTT.S163266.CrossRefPubMedPubMedCentral

49.

Calvisi DF, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–83. https://doi.org/10.1053/j.gastro.2010.12.006.CrossRefPubMed

50.

Wang MD, et al. Acetyl-coenzyme A carboxylase alpha promotion of glucose-mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients. Hepatology. 2016;63:1272–86. https://doi.org/10.1002/hep.28415.CrossRefPubMed

51.

Tomacha J, et al. Targeting fatty acid synthase modulates metabolic pathways and inhibits cholangiocarcinoma cell progression. Front Pharmacol. 2021;12: 696961. https://doi.org/10.3389/fphar.2021.696961.CrossRefPubMedPubMedCentral

52.

Xu D, et al. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature. 2020;580:530–5. https://doi.org/10.1038/s41586-020-2183-2.CrossRefPubMed

53.

Nelson ME, et al. Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival. Nat Commun. 2017;8:14689. https://doi.org/10.1038/ncomms14689.CrossRefPubMedPubMedCentral

54.

Nakagawa H, et al. Lipid metabolic reprogramming in hepatocellular carcinoma. Cancers Basel. 2018. https://doi.org/10.3390/cancers10110447.CrossRefPubMedPubMedCentral

55.

Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep. 2022;4: 100479. https://doi.org/10.1016/j.jhepr.2022.100479.CrossRefPubMedPubMedCentral

56.

Liang JQ, et al. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat Commun. 2018;9:4490. https://doi.org/10.1038/s41467-018-06931-6.CrossRefPubMedPubMedCentral

57.

Hall Z, et al. Lipid remodeling in hepatocyte proliferation and hepatocellular carcinoma. Hepatology. 2021;73:1028–44. https://doi.org/10.1002/hep.31391.CrossRefPubMed

58.

Jiang Y, et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature. 2019;567:257–61. https://doi.org/10.1038/s41586-019-0987-8.CrossRefPubMed

59.

Yang Z, et al. Cholesterol inhibits hepatocellular carcinoma invasion and metastasis by promoting CD44 localization in lipid rafts. Cancer Lett. 2018;429:66–77. https://doi.org/10.1016/j.canlet.2018.04.038.CrossRefPubMed

60.

Budhu A, et al. Integrated metabolite and gene expression profiles identify lipid biomarkers associated with progression of hepatocellular carcinoma and patient outcomes. Gastroenterology. 2013;144:1066–75. https://doi.org/10.1053/j.gastro.2013.01.054.CrossRefPubMed

61.

Murakami Y, et al. Comprehensive analysis of transcriptome and metabolome analysis in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma. Sci Rep. 2015;5:16294. https://doi.org/10.1038/srep16294.CrossRefPubMedPubMedCentral

62.

Missiaen R, et al. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment. Cell Metab. 2022;34:1151–67. https://doi.org/10.1016/j.cmet.2022.06.010.CrossRefPubMedPubMedCentral

63.

Mossmann D, et al. Arginine reprograms metabolism in liver cancer via RBM39. Cell. 2023;186:5068–83. https://doi.org/10.1016/j.cell.2023.09.011.CrossRefPubMedPubMedCentral

64.

Dai W, et al. OGDHL silencing promotes hepatocellular carcinoma by reprogramming glutamine metabolism. J Hepatol. 2020;72:909–23. https://doi.org/10.1016/j.jhep.2019.12.015.CrossRefPubMed

65.

Adebayo Michael AO, et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by beta-catenin mutations. Cell Metab. 2019;29:1135–50. https://doi.org/10.1016/j.cmet.2019.01.002.CrossRefPubMed

66.

Ding Z, et al. Metabolic pathway analyses identify proline biosynthesis pathway as a promoter of liver tumorigenesis. J Hepatol. 2020;72:725–35. https://doi.org/10.1016/j.jhep.2019.10.026.CrossRefPubMed

67.

Ducker GS, Rabinowitz JD. One-carbon metabolism in health and disease. Cell Metab. 2017;25:27–42. https://doi.org/10.1016/j.cmet.2016.08.009.CrossRefPubMed

68.

Newman AC, Maddocks ODK. One-carbon metabolism in cancer. Br J Cancer. 2017;116:1499–504. https://doi.org/10.1038/bjc.2017.118.CrossRefPubMedPubMedCentral

69.

Tedeschi PM, et al. Contribution of serine, folate and glycine metabolism to the ATP, NADPH and purine requirements of cancer cells. Cell Death Dis. 2013;4: e877. https://doi.org/10.1038/cddis.2013.393.CrossRefPubMedPubMedCentral

70.

Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572–83. https://doi.org/10.1038/nrc3557.CrossRefPubMedPubMedCentral

71.

Michelotti GA, Machado MV, Diehl AM. NAFLD, NASH and liver cancer. Nat Rev Gastroenterol Hepatol. 2013;10:656–65. https://doi.org/10.1038/nrgastro.2013.183.CrossRefPubMed

72.

Ren X, et al. The Protein Kinase Activity of NME7 Activates Wnt/beta-Catenin Signaling to Promote One-Carbon Metabolism in Hepatocellular Carcinoma. Cancer Res. 2022;82:60–74. https://doi.org/10.1158/0008-5472.CAN-21-1020.CrossRefPubMed

73.

Mukha D, et al. Glycine decarboxylase maintains mitochondrial protein lipoylation to support tumor growth. Cell Metab. 2022;34:775–82. https://doi.org/10.1016/j.cmet.2022.04.006.CrossRefPubMedPubMedCentral

74.

Li JT, et al. Dietary folate drives methionine metabolism to promote cancer development by stabilizing MAT IIA. Signal Transduct Target Ther. 2022;7:192. https://doi.org/10.1038/s41392-022-01017-8.CrossRefPubMedPubMedCentral

75.

Schulze K, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11. https://doi.org/10.1038/ng.3252.CrossRefPubMedPubMedCentral

76.

Nakamura H, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10. https://doi.org/10.1038/ng.3375.CrossRefPubMed

77.

Cancer Genome Atlas Research Network. Electronic address, w. b. e. & Cancer Genome Atlas Research, N. Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma. Cell 169, 1327–1341, https://doi.org/10.1016/j.cell.2017.05.046 (2017).

78.

Fernandez-Banet J, et al. Decoding complex patterns of genomic rearrangement in hepatocellular carcinoma. Genomics. 2014;103:189–203. https://doi.org/10.1016/j.ygeno.2014.01.003.CrossRefPubMed

79.

Baughman JM, et al. NeuCode proteomics reveals bap1 regulation of metabolism. Cell Rep. 2016;16:583–95. https://doi.org/10.1016/j.celrep.2016.05.096.CrossRefPubMedPubMedCentral

80.

Amann T, et al. GLUT1 expression is increased in hepatocellular carcinoma and promotes tumorigenesis. Am J Pathol. 2009;174:1544–52. https://doi.org/10.2353/ajpath.2009.080596.CrossRefPubMedPubMedCentral

81.

Kim YH, et al. SLC2A2 (GLUT2) as a novel prognostic factor for hepatocellular carcinoma. Oncotarget. 2017;8:68381–92. https://doi.org/10.18632/oncotarget.20266.CrossRefPubMedPubMedCentral

82.

Sun HW, et al. GLUT1 and ASCT2 as Predictors for Prognosis of Hepatocellular Carcinoma. PLoS ONE. 2016;11: e0168907. https://doi.org/10.1371/journal.pone.0168907.CrossRefPubMedPubMedCentral

83.

Kubo Y, et al. Different expression of glucose transporters in the progression of intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45:1610–7. https://doi.org/10.1016/j.humpath.2014.03.008.CrossRefPubMed

84.

Kim JW, Gao P, Liu YC, Semenza GL, Dang CV. Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 2007;27:7381–93. https://doi.org/10.1128/MCB.00440-07.CrossRefPubMedPubMedCentral

85.

Sun L, et al. cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions. Cell Res. 2015;25:429–44. https://doi.org/10.1038/cr.2015.33.CrossRefPubMedPubMedCentral

86.

Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 2004;64:2627–33. https://doi.org/10.1158/0008-5472.can-03-0846.CrossRefPubMed

87.

Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018;18:744–57. https://doi.org/10.1038/s41568-018-0074-8.CrossRefPubMed

88.

Perugorria MJ, et al. Wnt-beta-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16:121–36. https://doi.org/10.1038/s41575-018-0075-9.CrossRefPubMed

89.

Senni N, et al. beta-catenin-activated hepatocellular carcinomas are addicted to fatty acids. Gut. 2019;68:322–34. https://doi.org/10.1136/gutjnl-2017-315448.CrossRefPubMed

90.

Ikeno Y, et al. Preoperative metabolic tumor volume of intrahepatic cholangiocarcinoma measured by (18)F-FDG-PET is associated with the KRAS mutation status and prognosis. J Transl Med. 2018;16:95. https://doi.org/10.1186/s12967-018-1475-x.CrossRefPubMedPubMedCentral

91.

Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell. 2017;168:657–69. https://doi.org/10.1016/j.cell.2016.12.039.CrossRefPubMed

92.

Raggi C, Taddei ML, Rae C, Braconi C, Marra F. Metabolic reprogramming in cholangiocarcinoma. J Hepatol. 2022;77:849–64. https://doi.org/10.1016/j.jhep.2022.04.038.CrossRefPubMed

93.

Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39:1–10. https://doi.org/10.1016/j.immuni.2013.07.012.CrossRefPubMed

94.

Mellman I, Chen DS, Powles T, Turley SJ. The cancer-immunity cycle: Indication, genotype, and immunotype. Immunity. 2023;56:2188–205. https://doi.org/10.1016/j.immuni.2023.09.011.CrossRefPubMed

95.

Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41:421–33. https://doi.org/10.1016/j.ccell.2023.01.009.CrossRefPubMed

96.

Ho PC, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015;162:1217–28. https://doi.org/10.1016/j.cell.2015.08.012.CrossRefPubMedPubMedCentral

97.

Yu YR, et al. Disturbed mitochondrial dynamics in CD8(+) TILs reinforce T cell exhaustion. Nat Immunol. 2020;21:1540–51. https://doi.org/10.1038/s41590-020-0793-3.CrossRefPubMed

98.

Sullivan MR, et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife. 2019. https://doi.org/10.7554/eLife.44235.CrossRefPubMedPubMedCentral

99.

Chantranupong L, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell. 2016;165:153–64. https://doi.org/10.1016/j.cell.2016.02.035.CrossRefPubMedPubMedCentral

100.

Geiger R, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016;167:829–42. https://doi.org/10.1016/j.cell.2016.09.031.CrossRefPubMedPubMedCentral

101.

Wang W, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–4. https://doi.org/10.1038/s41586-019-1170-y.CrossRefPubMedPubMedCentral

102.

Fischer K, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–9. https://doi.org/10.1182/blood-2006-07-035972.CrossRefPubMed

103.

Elia I, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8(+) T cells. Cell Metab. 2022;34:1137–50. https://doi.org/10.1016/j.cmet.2022.06.008.CrossRefPubMedPubMedCentral

104.

Brand A, et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016;24:657–71. https://doi.org/10.1016/j.cmet.2016.08.011.CrossRefPubMed

105.

Dodard G, et al. Inflammation-Induced Lactate Leads to Rapid Loss of Hepatic Tissue-Resident NK Cells. Cell Rep. 2020;32: 107855. https://doi.org/10.1016/j.celrep.2020.107855.CrossRefPubMedPubMedCentral

106.

Zheng X, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol. 2019;20:1656–67. https://doi.org/10.1038/s41590-019-0511-1.CrossRefPubMed

107.

Watson MJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021;591:645–51. https://doi.org/10.1038/s41586-020-03045-2.CrossRefPubMedPubMedCentral

108.

Kumagai S, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell. 2022;40:201–18. https://doi.org/10.1016/j.ccell.2022.01.001.CrossRefPubMed

109.

Colegio OR, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–63. https://doi.org/10.1038/nature13490.CrossRefPubMedPubMedCentral

110.

Chaudagar K, et al. Reversal of Lactate and PD-1-mediated Macrophage Immunosuppression Controls Growth of PTEN/p53-deficient Prostate Cancer. Clin Cancer Res. 2023;29:1952–68. https://doi.org/10.1158/1078-0432.CCR-22-3350.CrossRefPubMedPubMedCentral

111.

Han S, et al. d-lactate modulates M2 tumor-associated macrophages and remodels immunosuppressive tumor microenvironment for hepatocellular carcinoma. Sci Adv. 2023;9:eadg2697. https://doi.org/10.1126/sciadv.adg2697.CrossRefPubMedPubMedCentral

112.

Zhao JL, et al. Notch-mediated lactate metabolism regulates MDSC development through the Hes1/MCT2/c-Jun axis. Cell Rep. 2022;38: 110451. https://doi.org/10.1016/j.celrep.2022.110451.CrossRefPubMed

113.

Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191:1486–95. https://doi.org/10.4049/jimmunol.1202702.CrossRefPubMed

114.

Yang X, et al. Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res. 2020;8:1440–51. https://doi.org/10.1158/2326-6066.CIR-20-0111.CrossRefPubMed

115.

Fallarino F, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9:1069–77. https://doi.org/10.1038/sj.cdd.4401073.CrossRefPubMed

116.

Mezrich JD, et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185:3190–8. https://doi.org/10.4049/jimmunol.0903670.CrossRefPubMed

117.

Holmgaard RB, et al. Tumor-expressed IDO recruits and activates MDSCs in a Treg-dependent manner. Cell Rep. 2015;13:412–24. https://doi.org/10.1016/j.celrep.2015.08.077.CrossRefPubMedPubMedCentral

118.

Bunse L, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018;24:1192–203. https://doi.org/10.1038/s41591-018-0095-6.CrossRefPubMed

119.

Notarangelo G, et al. Oncometabolite d-2HG alters T cell metabolism to impair CD8(+) T cell function. Science. 2022;377:1519–29. https://doi.org/10.1126/science.abj5104.CrossRefPubMedPubMedCentral

120.

Zelenay S, et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell. 2015;162:1257–70. https://doi.org/10.1016/j.cell.2015.08.015.CrossRefPubMedPubMedCentral

121.

Halford SER, et al. A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours. J Clin Oncol. 2017;35:2516–2516. https://doi.org/10.1200/JCO.2017.35.15_suppl.2516.CrossRef

122.

Girithar HN, et al. Involvement of the kynurenine pathway in breast cancer: updates on clinical research and trials. Br J Cancer. 2023;129:185–203. https://doi.org/10.1038/s41416-023-02245-7.CrossRefPubMedPubMedCentral

123.

Bendell JC, et al. Safety and efficacy of the anti-CD73 monoclonal antibody (mAb) oleclumab ± durvalumab in patients (pts) with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or EGFR-mutant non-small cell lung cancer (EGFRm NSCLC). J Clin Oncol. 2021;39:9047–9047. https://doi.org/10.1200/JCO.2021.39.15_suppl.9047.CrossRef

124.

DiNardo CD, et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J Clin Oncol. 2021;39:57–65. https://doi.org/10.1200/jco.20.01632.CrossRefPubMed

125.

Antonarakis ES, et al. Phase II, randomized, placebo-controlled trial of neoadjuvant celecoxib in men with clinically localized prostate cancer: evaluation of drug-specific biomarkers. J Clin Oncol. 2009;27:4986–93. https://doi.org/10.1200/jco.2009.21.9410.CrossRefPubMedPubMedCentral

126.

Altorki NK, et al. Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non–small-cell lung cancer. J Clin Oncol. 2003;21:2645–50. https://doi.org/10.1200/jco.2003.07.127.CrossRefPubMed

127.

Stine ZE, Schug ZT, Salvino JM, Dang CV. Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discov. 2022;21:141–62. https://doi.org/10.1038/s41573-021-00339-6.CrossRefPubMed

128.

Chen J, et al. Unbalanced glutamine partitioning between CD8T cells and cancer cells accompanied by immune cell dysfunction in hepatocellular carcinoma. Cells. 2022. https://doi.org/10.3390/cells11233924.CrossRefPubMedPubMedCentral

129.

Wang W, Guo MN, Li N, Pang DQ, Wu JH. Glutamine deprivation impairs function of infiltrating CD8(+) T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis. World J Gastrointest Oncol. 2022;14:1124–40. https://doi.org/10.4251/wjgo.v14.i6.1124.CrossRefPubMedPubMedCentral

130.

Davar D, et al. Phase Ib/II study of pembrolizumab and pegylated-interferon Alfa-2b in advanced melanoma. J Clin Oncol. 2018;36:JCO1800632. https://doi.org/10.1200/JCO.18.00632.CrossRefPubMed

131.

Hu B, et al. IFNalpha Potentiates Anti-PD-1 Efficacy by Remodeling Glucose Metabolism in the Hepatocellular Carcinoma Microenvironment. Cancer Discov. 2022;12:1718–41. https://doi.org/10.1158/2159-8290.CD-21-1022.CrossRefPubMed

132.

Handa P, et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol. 2019;105:1015–26. https://doi.org/10.1002/JLB.3A0318-108R.CrossRefPubMed

133.

Sun JL, et al. Tumor cell-imposed iron restriction drives immunosuppressive polarization of tumor-associated macrophages. J Transl Med. 2021;19:347. https://doi.org/10.1186/s12967-021-03034-7.CrossRefPubMedPubMedCentral

134.

Li Y, Mo H, Wu S, Liu X, Tu K. A novel lactate metabolism-related gene signature for predicting clinical outcome and tumor microenvironment in hepatocellular carcinoma. Front Cell Dev Biol. 2021;9: 801959. https://doi.org/10.3389/fcell.2021.801959.CrossRefPubMed

135.

Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol. 2021;21:151–61. https://doi.org/10.1038/s41577-020-0406-2.CrossRefPubMed

136.

Contreras-Baeza Y, et al. Monocarboxylate transporter 4 (MCT4) is a high affinity transporter capable of exporting lactate in high-lactate microenvironments. J Biol Chem. 2019;294:20135–47. https://doi.org/10.1074/jbc.RA119.009093.CrossRefPubMedPubMedCentral

137.

Fang Y, et al. Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology. 2023;77:109–23. https://doi.org/10.1002/hep.32348.CrossRefPubMed

138.

Xu M, et al. Tumor associated macrophages-derived exosomes facilitate hepatocellular carcinoma malignance by transferring lncMMPA to tumor cells and activating glycolysis pathway. J Exp Clin Cancer Res. 2022;41:253. https://doi.org/10.1186/s13046-022-02458-3.CrossRefPubMedPubMedCentral

139.

Gu J, et al. Tumor metabolite lactate promotes tumorigenesis by modulating MOESIN lactylation and enhancing TGF-beta signaling in regulatory T cells. Cell Rep. 2022;39: 110986. https://doi.org/10.1016/j.celrep.2022.110986.CrossRefPubMed

140.

Song BS, et al. Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2021-004337.CrossRefPubMedPubMedCentral

141.

Llovet JM, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. https://doi.org/10.1038/s41572-020-00240-3.CrossRefPubMed

142.

Deng H, et al. Tumor-derived lactate inhibit the efficacy of lenvatinib through regulating PD-L1 expression on neutrophil in hepatocellular carcinoma. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2020-002305.CrossRefPubMedPubMedCentral

143.

Ma C, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531:253–7. https://doi.org/10.1038/nature16969.CrossRefPubMedPubMedCentral

144.

Sun R, et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J Hepatol. 2022;77:453–66. https://doi.org/10.1016/j.jhep.2022.02.030.CrossRefPubMed

145.

Bayerl F, et al. Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses. Immunity. 2023;56:1341–58. https://doi.org/10.1016/j.immuni.2023.05.011.CrossRefPubMed

146.

Xun X, et al. Cyclooxygenase-2 expressed hepatocellular carcinoma induces cytotoxic T lymphocytes exhaustion through M2 macrophage polarization. Am J Transl Res. 2021;13:4360–75.PubMedPubMedCentral

147.

Lin J, et al. Multimodule characterization of immune subgroups in intrahepatic cholangiocarcinoma reveals distinct therapeutic vulnerabilities. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2022-004892.CrossRefPubMedPubMedCentral

148.

Lercher A, et al. Type I interferon signaling disrupts the hepatic urea cycle and alters systemic metabolism to suppress T cell function. Immunity. 2019;51:1074–87. https://doi.org/10.1016/j.immuni.2019.10.014.CrossRefPubMedPubMedCentral

149.

Cheu JW, et al. Hypoxia-inducible factor orchestrates adenosine metabolism to promote liver cancer development. Sci Adv. 2023;9:eade5111. https://doi.org/10.1126/sciadv.ade5111.CrossRefPubMedPubMedCentral

150.

Fu Y, et al. MicroRNA-223 attenuates hepatocarcinogenesis by blocking hypoxia-driven angiogenesis and immunosuppression. Gut. 2023;72:1942–58. https://doi.org/10.1136/gutjnl-2022-327924.CrossRefPubMed

151.

Wang J, et al. Tumor-derived adenosine promotes macrophage proliferation in human hepatocellular carcinoma. J Hepatol. 2021;74:627–37. https://doi.org/10.1016/j.jhep.2020.10.021.CrossRefPubMed

152.

Chen Y, et al. CXCR4 inhibition in tumor microenvironment facilitates anti-programmed death receptor-1 immunotherapy in sorafenib-treated hepatocellular carcinoma in mice. Hepatology. 2015;61:1591–602. https://doi.org/10.1002/hep.27665.CrossRefPubMed

153.

Suthen S, et al. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022;76:1329–44. https://doi.org/10.1002/hep.32419.CrossRefPubMed

154.

Cui C, et al. Hypoxia-inducible gene 2 promotes the immune escape of hepatocellular carcinoma from nature killer cells through the interleukin-10-STAT3 signaling pathway. J Exp Clin Cancer Res. 2019;38:229. https://doi.org/10.1186/s13046-019-1233-9.CrossRefPubMedPubMedCentral

155.

Wang S, et al. Blocking CD47 promotes antitumour immunity through CD103(+) dendritic cell-NK cell axis in murine hepatocellular carcinoma model. J Hepatol. 2022;77:467–78. https://doi.org/10.1016/j.jhep.2022.03.011.CrossRefPubMed

156.

Wang J, et al. Three-in-one oncolytic adenovirus system initiates a synergetic photodynamic immunotherapy in immune-suppressive cholangiocarcinoma. Small. 2023;19: e2207668. https://doi.org/10.1002/smll.202207668.CrossRefPubMed

157.

Wong AM, et al. Unique molecular characteristics of NAFLD-associated liver cancer accentuate beta-catenin/TNFRSF19-mediated immune evasion. J Hepatol. 2022;77:410–23. https://doi.org/10.1016/j.jhep.2022.03.015.CrossRefPubMed

158.

Totoki Y, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–73. https://doi.org/10.1038/ng.3126.CrossRefPubMed

159.

El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73. https://doi.org/10.1053/j.gastro.2011.12.061.CrossRefPubMed

160.

Le Duc D, et al. Reduced lipolysis in lipoma phenocopies lipid accumulation in obesity. Int J Obes (Lond). 2021;45:565–76. https://doi.org/10.1038/s41366-020-00716-y.CrossRefPubMed

161.

Sun H, et al. An inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma. Nat Commun. 2018;9:5214. https://doi.org/10.1038/s41467-018-07402-8.CrossRefPubMedPubMedCentral

162.

Wang N, et al. PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma. Signal Transduct Target Ther. 2021;6:86. https://doi.org/10.1038/s41392-021-00485-8.CrossRefPubMedPubMedCentral

163.

Yang Z, et al. Levels of pretreatment serum lipids predict responses to PD-1 inhibitor treatment in advanced intrahepatic cholangiocarcinoma. Int Immunopharmacol. 2023;115: 109687. https://doi.org/10.1016/j.intimp.2023.109687.CrossRefPubMed

164.

Lv H, et al. NAD(+) metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab. 2021;33:110–27. https://doi.org/10.1016/j.cmet.2020.10.021.CrossRefPubMed

165.

Wu MJ, et al. Mutant IDH Inhibits IFNgamma-TET2 Signaling to Promote Immunoevasion and Tumor Maintenance in Cholangiocarcinoma. Cancer Discov. 2022;12:812–35. https://doi.org/10.1158/2159-8290.CD-21-1077.CrossRefPubMedPubMedCentral

166.

Abou-Alfa GK, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21:796–807. https://doi.org/10.1016/S1470-2045(20)30157-1.CrossRefPubMedPubMedCentral

167.

Zhu AX, et al. Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol. 2021;39:266–266. https://doi.org/10.1200/JCO.2021.39.3_suppl.266.CrossRef

168.

Halford S, et al. A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer. Clin Cancer Res. 2023;29:1429–39. https://doi.org/10.1158/1078-0432.CCR-22-2263.CrossRefPubMedPubMedCentral

169.

Chu QS, et al. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors. Invest New Drugs. 2015;33:603–10. https://doi.org/10.1007/s10637-015-0221-y.CrossRefPubMed

170.

Sehdev A, et al. A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2018;82:309–17. https://doi.org/10.1007/s00280-018-3619-3.CrossRefPubMedPubMedCentral

171.

Molenaar RJ, et al. Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours. BMJ Open. 2017;7: e014961. https://doi.org/10.1136/bmjopen-2016-014961.CrossRefPubMedPubMedCentral

172.

Zhu AX, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol. 2021;7:1669–77. https://doi.org/10.1001/jamaoncol.2021.3836.CrossRefPubMed

173.

Lowery MA, et al. Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study. Lancet Gastroenterol Hepatol. 2019;4:711–20. https://doi.org/10.1016/S2468-1253(19)30189-X.CrossRefPubMedPubMedCentral

174.

Tap WD, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol. 2020;38:1693–701. https://doi.org/10.1200/JCO.19.02492.CrossRefPubMedPubMedCentral

175.

Jouve JL, et al. Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma. J Hepatol. 2019;71:516–22. https://doi.org/10.1016/j.jhep.2019.04.021.CrossRefPubMed

176.

Blanc JF, et al. Phase 2 trial comparing sorafenib, pravastatin, their combination or supportive care in HCC with Child-Pugh B cirrhosis. Hepatol Int. 2021;15:93–104. https://doi.org/10.1007/s12072-020-10120-3.CrossRefPubMed

177.

Riano I, et al. Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial). Cancers Basel. 2020. https://doi.org/10.3390/cancers12071900.CrossRefPubMedPubMedCentral

178.

Britten CD, et al. A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2017;23:4642–50. https://doi.org/10.1158/1078-0432.CCR-16-2363.CrossRefPubMedPubMedCentral

179.

Giles JR, Globig AM, Kaech SM, Wherry EJ. CD8(+) T cells in the cancer-immunity cycle. Immunity. 2023;56:2231–53. https://doi.org/10.1016/j.immuni.2023.09.005.CrossRefPubMed

180.

Wang H, et al. Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis. J Hepatol. 2021;75:1271–83. https://doi.org/10.1016/j.jhep.2021.07.032.CrossRefPubMed

181.

Pfister D, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450–6. https://doi.org/10.1038/s41586-021-03362-0.CrossRefPubMedPubMedCentral

182.

Wabitsch S, et al. Metformin treatment rescues CD8(+) T-cell response to immune checkpoint inhibitor therapy in mice with NAFLD. J Hepatol. 2022;77:748–60. https://doi.org/10.1016/j.jhep.2022.03.010.CrossRefPubMedPubMedCentral

183.

Kotsiliti E, et al. Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling. J Hepatol. 2023;79:296–313. https://doi.org/10.1016/j.jhep.2023.04.037.CrossRefPubMedPubMedCentral

184.

Qin WH, et al. High serum levels of cholesterol increase antitumor functions of nature killer cells and reduce growth of liver tumors in mice. Gastroenterology. 2020;158:1713–27. https://doi.org/10.1053/j.gastro.2020.01.028.CrossRefPubMed

185.

Chen DP, et al. Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma. J Hepatol. 2019;71:333–43. https://doi.org/10.1016/j.jhep.2019.04.007.CrossRefPubMed

186.

Peng ZP, et al. Glycolytic activation of monocytes regulates the accumulation and function of neutrophils in human hepatocellular carcinoma. J Hepatol. 2020;73:906–17. https://doi.org/10.1016/j.jhep.2020.05.004.CrossRefPubMed

187.

Ning WR, et al. Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma. J Clin Invest. 2022. https://doi.org/10.1172/JCI153110.CrossRefPubMedPubMedCentral

188.

Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol. 2011;6:275–97. https://doi.org/10.1146/annurev-pathol-011110-130138.CrossRefPubMedPubMedCentral

189.

Wu L, et al. RIPK3 orchestrates fatty acid metabolism in tumor-associated macrophages and hepatocarcinogenesis. Cancer Immunol Res. 2020;8:710–21. https://doi.org/10.1158/2326-6066.CIR-19-0261.CrossRefPubMed

190.

Zhang J, et al. Hypoxia-inducible factor-1alpha/interleukin-1beta signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. 2018;67:1872–89. https://doi.org/10.1002/hep.29681.CrossRefPubMed

191.

Lu LG, et al. PD-L1 blockade liberates intrinsic antitumourigenic properties of glycolytic macrophages in hepatocellular carcinoma. Gut. 2022;71:2551–60. https://doi.org/10.1136/gutjnl-2021-326350.CrossRefPubMed

192.

Liu J, et al. Integrative metabolomic characterisation identifies altered portal vein serum metabolome contributing to human hepatocellular carcinoma. Gut. 2022;71:1203–13. https://doi.org/10.1136/gutjnl-2021-325189.CrossRefPubMed

193.

Daniel N, et al. The role of the gut microbiome in the development of hepatobiliary cancers. Hepatology. 2023. https://doi.org/10.1097/HEP.0000000000000406.CrossRefPubMed

194.

Silveira MAD, Bilodeau S, Greten TF, Wang XW, Trinchieri G. The gut-liver axis: host microbiota interactions shape hepatocarcinogenesis. Trends Cancer. 2022;8:583–97. https://doi.org/10.1016/j.trecan.2022.02.009.CrossRefPubMedPubMedCentral

195.

Bauer KC, Littlejohn PT, Ayala V, Creus-Cuadros A, Finlay BB. Nonalcoholic Fatty liver disease and the gut-liver axis: exploring an undernutrition perspective. Gastroenterology. 2022;162:1858–75. https://doi.org/10.1053/j.gastro.2022.01.058.CrossRefPubMed

196.

Yu LX, Schwabe RF. The gut microbiome and liver cancer: mechanisms and clinical translation. Nat Rev Gastroenterol Hepatol. 2017;14:527–39. https://doi.org/10.1038/nrgastro.2017.72.CrossRefPubMedPubMedCentral

197.

Bi C, et al. Molecular Immune Mechanism of Intestinal Microbiota and Their Metabolites in the Occurrence and Development of Liver Cancer. Front Cell Dev Biol. 2021;9: 702414. https://doi.org/10.3389/fcell.2021.702414.CrossRefPubMedPubMedCentral

198.

Yoshimoto S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499:97–101. https://doi.org/10.1038/nature12347.CrossRefPubMed

199.

Zhang X, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021;70:761–74. https://doi.org/10.1136/gutjnl-2019-319664.CrossRefPubMed

200.

Zhou P, et al. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. Cell Metab. 2023;35:1961–75. https://doi.org/10.1016/j.cmet.2023.09.009.CrossRefPubMed

201.

Blaak EE, et al. Short chain fatty acids in human gut and metabolic health. Benef Microbes. 2020;11:411–55. https://doi.org/10.3920/BM2020.0057.CrossRefPubMed

202.

Che Y, et al. Gut microbial metabolite butyrate improves anticancer therapy by regulating intracellular calcium homeostasis. Hepatology. 2023;78:88–102. https://doi.org/10.1097/HEP.0000000000000047.CrossRefPubMed

203.

Zhang Q, et al. Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma. Cancer Discov. 2021;11:1248–67. https://doi.org/10.1158/2159-8290.CD-20-0304.CrossRefPubMed

204.

Ren Z, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut. 2019;68:1014–23. https://doi.org/10.1136/gutjnl-2017-315084.CrossRefPubMed

205.

Jia X, et al. Characterization of Gut Microbiota, Bile Acid Metabolism, and Cytokines in Intrahepatic Cholangiocarcinoma. Hepatology. 2020;71:893–906. https://doi.org/10.1002/hep.30852.CrossRefPubMed

206.

Huang H, et al. Integrated analysis of microbiome and host transcriptome reveals correlations between gut microbiota and clinical outcomes in HBV-related hepatocellular carcinoma. Genome Med. 2020;12:102. https://doi.org/10.1186/s13073-020-00796-5.CrossRefPubMedPubMedCentral

207.

Schneider KM, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun. 2022;13:3964. https://doi.org/10.1038/s41467-022-31312-5.CrossRefPubMedPubMedCentral

208.

Behary J, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12:187. https://doi.org/10.1038/s41467-020-20422-7.CrossRefPubMedPubMedCentral

209.

Protzer U, Maini MK, Knolle PA. Living in the liver: hepatic infections. Nat Rev Immunol. 2012;12:201–13. https://doi.org/10.1038/nri3169.CrossRefPubMed

210.

Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol. 2013;14:996–1006. https://doi.org/10.1038/ni.2691.CrossRefPubMed

211.

Ma C, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018. https://doi.org/10.1126/science.aan5931.CrossRefPubMedPubMedCentral

212.

Schramm C. Bile Acids, the Microbiome, Immunity, and Liver Tumors. N Engl J Med. 2018;379:888–90. https://doi.org/10.1056/NEJMcibr1807106.CrossRefPubMed

213.

Dart A. Gut microbiota bile acid metabolism controls cancer immunosurveillance. Nat Rev Microbiol. 2018;16:453. https://doi.org/10.1038/s41579-018-0053-9.CrossRefPubMed

214.

Ji G, et al. Manipulating Liver Bile Acid Signaling by Nanodelivery of Bile Acid Receptor Modulators for Liver Cancer Immunotherapy. Nano Lett. 2021;21:6781–91. https://doi.org/10.1021/acs.nanolett.1c01360.CrossRefPubMed

215.

Hang S, et al. Bile acid metabolites control T(H)17 and T(reg) cell differentiation. Nature. 2019;576:143–8. https://doi.org/10.1038/s41586-019-1785-z.CrossRefPubMedPubMedCentral

216.

Campbell C, et al. Bacterial metabolism of bile acids promotes generation of peripheral regulatory T cells. Nature. 2020;581:475–9. https://doi.org/10.1038/s41586-020-2193-0.CrossRefPubMedPubMedCentral

217.

Paik D, et al. Human gut bacteria produce Tau(Eta)17-modulating bile acid metabolites. Nature. 2022;603:907–12. https://doi.org/10.1038/s41586-022-04480-z.CrossRefPubMedPubMedCentral

218.

Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. https://doi.org/10.1126/science.aan4236.CrossRefPubMed

219.

Routy B, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7. https://doi.org/10.1126/science.aan3706.CrossRefPubMed

220.

Zheng Y, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer. 2019;7:193. https://doi.org/10.1186/s40425-019-0650-9.CrossRefPubMedPubMedCentral

221.

Mao J, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer. 2021. https://doi.org/10.1136/jitc-2021-003334.CrossRefPubMedPubMedCentral

222.

Loeuillard E, et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J Clin Invest. 2020;130:5380–96. https://doi.org/10.1172/JCI137110.CrossRefPubMedPubMedCentral

223.

Pan B, et al. 2,5-dimethylcelecoxib alleviated NK and T-cell exhaustion in hepatocellular carcinoma via the gastrointestinal microbiota-AMPK-mTOR axis. J Immunother Cancer. 2023. https://doi.org/10.1136/jitc-2023-006817.CrossRefPubMedPubMedCentral

224.

Loo TM, et al. Gut microbiota promotes obesity-associated liver cancer through PGE(2)-Mediated Suppression of Antitumor immunity. Cancer Discov. 2017;7:522–38. https://doi.org/10.1158/2159-8290.CD-16-0932.CrossRefPubMed

225.

Bonavita E, et al. Antagonistic Inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity. 2020;53:1215–29. https://doi.org/10.1016/j.immuni.2020.10.020.CrossRefPubMedPubMedCentral

226.

Pelly VS, et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discov. 2021;11:2602–19. https://doi.org/10.1158/2159-8290.CD-20-1815.CrossRefPubMedPubMedCentral

227.

Hu C, et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology. 2023;77:48–64. https://doi.org/10.1002/hep.32449.CrossRefPubMed

228.

McDonald B, et al. Programing of an intravascular immune firewall by the gut microbiota protects against pathogen dissemination during infection. Cell Host Microbe. 2020;28:660–8. https://doi.org/10.1016/j.chom.2020.07.014.CrossRefPubMed

229.

Lee PC, et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunother Cancer. 2022. https://doi.org/10.1136/jitc-2022-004779.CrossRefPubMedPubMedCentral

230.

Rautiainen S, Manson JE, Lichtenstein AH, Sesso HD. Dietary supplements and disease prevention - a global overview. Nat Rev Endocrinol. 2016;12:407–20. https://doi.org/10.1038/nrendo.2016.54.CrossRefPubMed

231.

Singh V, et al. Dysregulated Microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 2018;175:679–94. https://doi.org/10.1016/j.cell.2018.09.004.CrossRefPubMedPubMedCentral

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Metabolic reprogramming in the tumor microenvironment of liver cancer

Abstract

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

ChatGPT’s ability to generate realistic experimental images poses a new challenge to academic integrity

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy

Off-the-shelf CAR-T cell therapies for relapsed or refractory B-cell malignancies: latest update from ASH 2023 annual meeting

FFAR2 expressing myeloid-derived suppressor cells drive cancer immunoevasion

Critical role of the gut microbiota in immune responses and cancer immunotherapy

Perioperative versus adjuvant S-1 plus oxaliplatin chemotherapy for stage II/III resectable gastric cancer (RESONANCE): a randomized, open-label, phase 3 trial

Keynote webinar | Spotlight on antibody–drug conjugates in cancer