The Role of Metabolic Reprogramming in the Tumor Immune Microenvironment: Mechanisms and Opportunities for Immunotherapy in Hepatocellular Carcinoma

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Jun 19

PMID 38891772

Authors

Nan Hu

Haiyang Li

Changcheng Tao

Ting Xiao

Weiqi Rong

Affiliations

Soon will be listed here.

Abstract

As one of the emerging hallmarks of tumorigenesis and tumor progression, metabolic remodeling is common in the tumor microenvironment. Hepatocellular carcinoma (HCC) is the third leading cause of global tumor-related mortality, causing a series of metabolic alterations in response to nutrient availability and consumption to fulfill the demands of biosynthesis and carcinogenesis. Despite the efficacy of immunotherapy in treating HCC, the response rate remains unsatisfactory. Recently, research has focused on metabolic reprogramming and its effects on the immune state of the tumor microenvironment, and immune response rate. In this review, we delineate the metabolic reprogramming observed in HCC and its influence on the tumor immune microenvironment. We discuss strategies aimed at enhancing response rates and overcoming immune resistance through metabolic interventions, focusing on targeting glucose, lipid, or amino acid metabolism, as well as systemic regulation.

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References

Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y . Lactate-Modulated Immunosuppression of Myeloid-Derived Suppressor Cells Contributes to the Radioresistance of Pancreatic Cancer. Cancer Immunol Res. 2020; 8(11):1440-1451. DOI: 10.1158/2326-6066.CIR-20-0111. View

Furihata T, Sawada T, Kita J, Iso Y, Kato M, Rokkaku K . Serum alpha-fetoprotein level per tumor volume reflects prognosis in patients with hepatocellular carcinoma after curative hepatectomy. Hepatogastroenterology. 2008; 55(86-87):1705-9. View

Brand A, Singer K, Koehl G, Kolitzus M, Schoenhammer G, Thiel A . 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. View

Li B, Li Y, Zhou H, Xu Y, Cao Y, Cheng C . Multiomics identifies metabolic subtypes based on fatty acid degradation allocating personalized treatment in hepatocellular carcinoma. Hepatology. 2023; 79(2):289-306. PMC: 10789383. DOI: 10.1097/HEP.0000000000000553. View

Sangro B, Sarobe P, Hervas-Stubbs S, Melero I . Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021; 18(8):525-543. PMC: 8042636. DOI: 10.1038/s41575-021-00438-0. View

Che L, Chi W, Qiao Y, Zhang J, Song X, Liu Y . Cholesterol biosynthesis supports the growth of hepatocarcinoma lesions depleted of fatty acid synthase in mice and humans. Gut. 2019; 69(1):177-186. PMC: 6943247. DOI: 10.1136/gutjnl-2018-317581. View

Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers W . New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002; 21(54):8293-301. DOI: 10.1038/sj.onc.1206118. View

Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman D, Moinard C . Apc tumor suppressor gene is the "zonation-keeper" of mouse liver. Dev Cell. 2006; 10(6):759-70. DOI: 10.1016/j.devcel.2006.03.015. View

Li B, Cao Y, Meng G, Qian L, Xu T, Yan C . Targeting glutaminase 1 attenuates stemness properties in hepatocellular carcinoma by increasing reactive oxygen species and suppressing Wnt/beta-catenin pathway. EBioMedicine. 2018; 39:239-254. PMC: 6355660. DOI: 10.1016/j.ebiom.2018.11.063. View

10.

Huang H, Tsui Y, Ng I . Fueling HCC Dynamics: Interplay Between Tumor Microenvironment and Tumor Initiating Cells. Cell Mol Gastroenterol Hepatol. 2023; 15(5):1105-1116. PMC: 10036749. DOI: 10.1016/j.jcmgh.2023.01.007. View

11.

Cramer T . Impact of dietary carbohydrate restriction on the pathobiology of Hepatocellular Carcinoma: The gut-liver axis and beyond. Semin Immunol. 2023; 66:101736. DOI: 10.1016/j.smim.2023.101736. View

12.

Baruch E, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L . Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2020; 371(6529):602-609. DOI: 10.1126/science.abb5920. View

13.

Zhu G, Tang Z, Huang R, Qu W, Fang Y, Yang R . CD36 cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor. Cell Discov. 2023; 9(1):25. PMC: 9988869. DOI: 10.1038/s41421-023-00529-z. View

14.

Weber D, Aminazdeh-Gohari S, Kofler B . Ketogenic diet in cancer therapy. Aging (Albany NY). 2018; 10(2):164-165. PMC: 5842847. DOI: 10.18632/aging.101382. View

15.

Lee P, Wu C, Hung Y, Lee C, Chi C, Lee I . Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunother Cancer. 2022; 10(6). PMC: 9226985. DOI: 10.1136/jitc-2022-004779. View

16.

Corrado M, Edwards-Hicks J, Villa M, Flachsmann L, Sanin D, Jacobs M . Dynamic Cardiolipin Synthesis Is Required for CD8 T Cell Immunity. Cell Metab. 2020; 32(6):981-995.e7. PMC: 7721104. DOI: 10.1016/j.cmet.2020.11.003. View

17.

Mead J, Irvine S, Ramji D . Lipoprotein lipase: structure, function, regulation, and role in disease. J Mol Med (Berl). 2002; 80(12):753-69. DOI: 10.1007/s00109-002-0384-9. View

18.

Gu X, Wei H, Suo C, Shen S, Zhu C, Chen L . Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8 T-cell exhaustion. Nat Commun. 2023; 14(1):8154. PMC: 10710408. DOI: 10.1038/s41467-023-43988-4. View

19.

Liu Y, Zhao T, Li Z, Wang L, Yuan S, Sun L . The role of ASCT2 in cancer: A review. Eur J Pharmacol. 2018; 837:81-87. DOI: 10.1016/j.ejphar.2018.07.007. View

20.

Rimassa L, Finn R, Sangro B . Combination immunotherapy for hepatocellular carcinoma. J Hepatol. 2023; 79(2):506-515. DOI: 10.1016/j.jhep.2023.03.003. View