Image Info

Figure 2.

Immune cells in HCC tumors affecting cholesterol context. Differential effects of cholesterol in myeloid and lymphoid cells inside TIME in HCC. Black arrows indicate recruitment or activation, and flattened red lines indicate exhaustion or inactivity state leucocytes. M2 macrophages studied in ovarian cancer release cholesterol and provide aggressivity to the cancer cells. Cholesterol reduces cytotoxic activity in CD8⁺ T cells (CTL CD8⁺) through endoplasmic reticulum (ER) stress and affects antigen-presenting in dendritic cells (DC). In more cases, cholesterol promotes the recruitment and activation of different immune cells. Created with BioRender.com. CCL3: C-C motif chemokine ligand 3; G-CSF: granulocyte-colony stimulator factor; IFNγ: interferon gamma; MCP-1: monocyte chemoattractant protein-1

Declarations

Author contributions

AEC conceptualized the manuscript, wrote the draft, and revised the final manuscript. LCR and ASN wrote and revised the draft. VSA and RUML provided the input in writing the paper. LEGQ conceptualized the manuscript and revised the draft and the final manuscript. MCGR conceptualized the manuscript, designed the outline, and coordinated the writing and financial support.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was funded by “Universidad Autónoma Metropolitana” and “Conacyt-Fronteras de la Ciencia-1320”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. [DOI] [PubMed]

Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. [DOI] [PubMed]

Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589–604. [DOI] [PubMed] [PMC]

Gomez-Quiroz LE, Roman S. Influence of genetic and environmental risk factors in the development of hepatocellular carcinoma in Mexico. Ann Hepatol. 2022;27:100649. [DOI] [PubMed]

Simoni-Nieves A, Salas-Silva S, Chávez-Rodríguez L, Escobedo-Calvario A, Desoteux M, Bucio L, et al. The consumption of cholesterol-enriched diets conditions the development of a subtype of HCC with high aggressiveness and poor prognosis. Cancers (Basel). 2021;13:1721. [DOI] [PubMed] [PMC]

Pérez-Aguilar B, Vidal CJ, Palomec G, García-Dolores F, Gutiérrez-Ruiz MC, Bucio L, et al. Acetylcholinesterase is associated with a decrease in cell proliferation of hepatocellular carcinoma cells. Biochim Biophys Acta. 2015;1852:1380–7. [DOI] [PubMed]

Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140:1071–83.E5. [DOI] [PubMed] [PMC]

Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30:R921–5. [DOI] [PubMed] [PMC]

Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM. Resolution of inflammation: what controls its onset? Front Immunol. 2016;7:160. [DOI] [PubMed] [PMC]

10.

Zhong X, Lee HN, Kim SH, Park SA, Kim W, Cha YN, et al. Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation. FASEB J. 2018;32:5312–25. [DOI] [PubMed]

11.

Dhamija E, Paul SB, Kedia S. Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: an increasing concern. Indian J Med Res. 2019;149:9–17. [DOI] [PubMed] [PMC]

12.

Butler LM, Perone Y, Dehairs J, Lupien LE, de Laat V, Talebi A, et al. Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev. 2020;159:245–93. [DOI] [PubMed] [PMC]

13.

Enríquez-Cortina C, Bello-Monroy O, Rosales-Cruz P, Souza V, Miranda RU, Toledo-Pérez R, et al. Cholesterol overload in the liver aggravates oxidative stress-mediated DNA damage and accelerates hepatocarcinogenesis. Oncotarget. 2017;8:104136–48. [DOI] [PubMed] [PMC]

14.

Sun Y, Sukumaran P, Varma A, Derry S, Sahmoun AE, Singh BB. Cholesterol-induced activation of TRPM7 regulates cell proliferation, migration, and viability of human prostate cells. Biochim Biophys Acta. 2014;1843:1839–50. [DOI] [PubMed] [PMC]

15.

Domínguez-Pérez M, Simoni-Nieves A, Rosales P, Nuño-Lámbarri N, Rosas-Lemus M, Souza V, et al. Cholesterol burden in the liver induces mitochondrial dynamic changes and resistance to apoptosis. J Cell Physiol. 2019;234:7213–23. [DOI] [PubMed]

16.

Kusnadi A, Park SH, Yuan R, Pannellini T, Giannopoulou E, Oliver D, et al. The cytokine TNF promotes transcription factor SREBP activity and binding to inflammatory genes to activate macrophages and limit tissue repair. Immunity. 2019;51:241–57.E9. [DOI] [PubMed] [PMC]

17.

Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden CDCC, Li Y, et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell. 2018;172:135–46.E9. [DOI] [PubMed]

18.

Chew V, Toh HC, Abastado JP. Immune microenvironment in tumor progression: characteristics and challenges for therapy. J Oncol. 2012;2012:608406. [DOI] [PubMed] [PMC]

19.

Desai R, Coxon AT, Dunn GP. Therapeutic applications of the cancer immunoediting hypothesis. Semin Cancer Biol. 2022;78:63–77. [DOI] [PubMed]

20.

Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002;3:991–8. [DOI] [PubMed]

21.

Fridman WH, Dieu-Nosjean MC, Pagès F, Cremer I, Damotte D, Sautès-Fridman C, et al. The immune microenvironment of human tumors: general significance and clinical impact. Cancer Microenviron. 2013;6:117–22. [DOI] [PubMed] [PMC]

22.

Garcia-Ruiz C, Conde de la Rosa L, Ribas V, Fernandez-Checa JC. Mitochondrial cholesterol and cancer. Semin Cancer Biol. 2021;73:76–85. [DOI] [PubMed] [PMC]

23.

Xue L, Qi H, Zhang H, Ding L, Huang Q, Zhao D, et al. Targeting SREBP-2-regulated mevalonate metabolism for cancer therapy. Front Oncol. 2020;10:1510. [DOI] [PubMed] [PMC]

24.

Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015;15:104–16. [DOI] [PubMed] [PMC]

25.

Ioannou GN. The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol Metab. 2016;27:84–95. [DOI] [PubMed]

26.

Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29:431–8. [DOI] [PubMed] [PMC]

27.

Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn S, et al. Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages. J Biol Chem. 2002;277:49982–8. [DOI] [PubMed]

28.

Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019;29:1376–89.E4. [DOI] [PubMed]

29.

Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2:6. [DOI] [PubMed] [PMC]

30.

He M, Zhang W, Dong Y, Wang L, Fang T, Tang W, et al. Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells. J Exp Clin Cancer Res. 2017;36:15. [DOI] [PubMed] [PMC]

31.

Bakiri L, Hamacher R, Graña O, Guío-Carrión A, Campos-Olivas R, Martinez L, et al. Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation. J Exp Med. 2017;214:1387–409. [DOI] [PubMed] [PMC]

32.

Simoes Eugénio M, Farooq M, Dion S, Devisme C, Raguenes-Nicol C, Piquet-Pellorce C, et al. Hepatocellular carcinoma emergence in diabetic mice with non-alcoholic steatohepatitis depends on diet and is delayed in liver exhibiting an active immune response. Cancers (Basel). 2020;12:1491. [DOI] [PubMed] [PMC]

33.

Liang JQ, Teoh N, Xu L, Pok S, Li X, Chu ESH, et al. Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat Commun. 2018;9:4490. [DOI] [PubMed] [PMC]

34.

Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140:197–208. [DOI] [PubMed] [PMC]

35.

Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer. 2017;3:56–71. [DOI] [PubMed]

36.

Bévant K, Desoteux M, Angenard G, Pineau R, Caruso S, Louis C, et al. TGFβ-induced FOXS1 controls epithelial-mesenchymal transition and predicts a poor prognosis in liver cancer. Hepatol Commun. 2022;6:1157–71. [DOI] [PubMed] [PMC]

37.

Chen J, Gingold JA, Su X. Immunomodulatory TGF-β signaling in hepatocellular carcinoma. Trends Mol Med. 2019;25:1010–23. [DOI] [PubMed]

38.

Zhang F, Wang H, Wang X, Jiang G, Liu H, Zhang G, et al. TGF-β induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget. 2016;7:52294–306. [DOI] [PubMed] [PMC]

39.

Yamane T, Muramatsu A, Shimura M, Kobayashi-Hattori K, Oishi Y. Transforming growth factor-β1 induces cholesterol synthesis by increasing HMG-CoA reductase mRNA expression in keratinocytes. Biosci Biotechnol Biochem. 2016;80:1379–81. [DOI] [PubMed]

40.

Fezza M, Moussa M, Aoun R, Haber R, Hilal G. DKK1 promotes hepatocellular carcinoma inflammation, migration and invasion: implication of TGF-β1. PLoS One. 2019;14:e0223252. [DOI] [PubMed] [PMC]

41.

Zhang Q, He Y, Luo N, Patel SJ, Han Y, Gao R, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell. 2019;179:829–45.E20. [DOI] [PubMed]

42.

Foerster F, Hess M, Gerhold-Ay A, Marquardt JU, Becker D, Galle PR, et al. The immune contexture of hepatocellular carcinoma predicts clinical outcome. Sci Rep. 2018;8:5351. [DOI] [PubMed] [PMC]

43.

Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450–6. [DOI] [PubMed] [PMC]

44.

Nishida N, Kudo M. Immunological microenvironment of hepatocellular carcinoma and its clinical implication. Oncology. 2017;92:40–9. [DOI] [PubMed]

45.

Shono S, Habu Y, Nakashima M, Sato A, Nakashima H, Miyazaki H, et al. The immunologic outcome of enhanced function of mouse liver lymphocytes and Kupffer cells by high-fat and high-cholesterol diet. Shock. 2011;36:484–93. [DOI] [PubMed]

46.

Tian Z, Hou X, Liu W, Han Z, Wei L. Macrophages and hepatocellular carcinoma. Cell Biosci. 2019;9:79. [DOI] [PubMed] [PMC]

47.

de Oliveira S, Houseright RA, Graves AL, Golenberg N, Korte BG, Miskolci V, et al. High cholesterol diet modulates macrophage polarization and liver inflammation during early hepatocellular carcinoma progression in zebrafish. bioRxiv: 10.1101/299016 [Preprint]. 2018 [cited 2022 Feb 15]: [38 p.]. Available from: https://www.biorxiv.org/content/10.1101/299016v1

48.

Zhang Q, Wang H, Mao C, Sun M, Dominah G, Chen L, et al. Fatty acid oxidation contributes to IL-1β secretion in M2 macrophages and promotes macrophage-mediated tumor cell migration. Mol Immunol. 2018;94:27–35. [DOI] [PubMed] [PMC]

49.

Bao D, Zhao J, Zhou X, Yang Q, Chen Y, Zhu J, et al. Mitochondrial fission-induced mtDNA stress promotes tumor-associated macrophage infiltration and HCC progression. Oncogene. 2019;38:5007–20. [DOI] [PubMed] [PMC]

50.

Delire B, Henriet P, Lemoine P, Leclercq IA, Stärkel P. Chronic liver injury promotes hepatocarcinoma cell seeding and growth, associated with infiltration by macrophages. Cancer Sci. 2018;109:2141–52. [DOI] [PubMed] [PMC]

51.

Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology. 2018;67:1270–83. [DOI] [PubMed]

52.

Ambade A, Satishchandran A, Saha B, Gyongyosi B, Lowe P, Kodys K, et al. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10. Oncoimmunology. 2016;5:e1221557. [DOI] [PubMed] [PMC]

53.

Liang S, Ma HY, Zhong Z, Dhar D, Liu X, Xu J, et al. NADPH oxidase 1 in liver macrophages promotes inflammation and tumor development in mice. Gastroenterology. 2019;156:1156–72.E6. [DOI] [PubMed] [PMC]

54.

Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16:3420–30. [DOI] [PubMed]

55.

Mukaida N, Sasaki SI, Baba T. Two-faced roles of tumor-associated neutrophils in cancer development and progression. Int J Mol Sci. 2020;21:3457. [DOI] [PubMed] [PMC]

56.

Masucci MT, Minopoli M, Carriero MV. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Front Oncol. 2019;9:1146. [DOI] [PubMed] [PMC]

57.

Yang LY, Luo Q, Lu L, Zhu WW, Sun HT, Wei R, et al. Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020;13:3. [DOI] [PubMed] [PMC]

58.

Raccosta L, Fontana R, Maggioni D, Lanterna C, Villablanca EJ, Paniccia A, et al. The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J Exp Med. 2013;210:1711–28. [DOI] [PubMed] [PMC]

59.

Shi SZ, Lee EJ, Lin YJ, Chen L, Zheng HY, He XQ, et al. Recruitment of monocytes and epigenetic silencing of intratumoral CYP7B1 primarily contribute to the accumulation of 27-hydroxycholesterol in breast cancer. Am J Cancer Res. 2019;9:2194–208. [PubMed] [PMC]

60.

Michael C, Martínez-Navarro FJ, de Oliveira S. Analysis of liver microenvironment during early progression of non-alcoholic fatty liver disease-associated hepatocellular carcinoma in zebrafish. J Vis Exp. 2021:e62457. [DOI] [PubMed]

61.

Mantovani A. Macrophages, neutrophils, and cancer: a double edged sword. New J Sci. 2014;2014:271940. [DOI]

62.

Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018;9:1869. [DOI] [PubMed] [PMC]

63.

Qin WH, Yang ZS, Li M, Chen Y, Zhao XF, Qin YY, 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. [DOI] [PubMed]

64.

Fu S, He K, Tian C, Sun H, Zhu C, Bai S, et al. Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells. Nat Commun. 2020;11:438. [DOI] [PubMed] [PMC]

65.

Streba LA, Streba CT, Săndulescu L, Vere CC, Mitruţ P, Cotoi BV, et al. Dendritic cells and hepatocellular carcinoma. Rom J Morphol Embryol. 2014;55:1287–93. [PubMed]

66.

Zhou ZJ, Xin HY, Li J, Hu ZQ, Luo CB, Zhou SL. Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection. Cancer Immunol Immunother. 2019;68:1223–33. [DOI] [PubMed]

67.

Cao W, Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol. 2014;192:2920–31. [DOI] [PubMed] [PMC]

68.

Villablanca EJ, Raccosta L, Zhou D, Fontana R, Maggioni D, Negro A, et al. Tumor-mediated liver X receptor-α activation inhibits CC chemokine receptor-7 expression on dendritic cells and dampens antitumor responses. Nat Med. 2010;16:98–105. [DOI] [PubMed]

69.

Hasegawa K, Noguchi Y, Koizumi F, Uenaka A, Tanaka M, Shimono M, et al. In vitro stimulation of CD8 and CD4 T cells by dendritic cells loaded with a complex of cholesterol-bearing hydrophobized pullulan and NY-ESO-1 protein: identification of a new HLA-DR15-binding CD4 T-cell epitope. Clin Cancer Res. 2006;12:1921–7. [DOI] [PubMed]

70.

Ji L, Gu J, Chen L, Miao D. Changes of Th1/Th2 cytokines in patients with primary hepatocellular carcinoma after ultrasound-guided ablation. Int J Clin Exp Pathol. 2017;10:8715–20. [PubMed] [PMC]

71.

Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48:202–13. [DOI] [PubMed] [PMC]

72.

Van Herck MA, Weyler J, Kwanten WJ, Dirinck EL, De Winter BY, Francque SM, et al. The differential roles of T cells in non-alcoholic fatty liver disease and obesity. Front Immunol. 2019;10:82. [DOI] [PubMed] [PMC]

73.

Tsuchida T, Lee YA, Fujiwara N, Ybanez M, Allen B, Martins S, et al. A simple diet- and chemical-induced murine NASH model with rapid progression of steatohepatitis, fibrosis and liver cancer. J Hepatol. 2018;69:385–95. [DOI] [PubMed] [PMC]

74.

Ma X, Bi E, Lu Y, Su P, Huang C, Liu L, et al. Cholesterol induces CD8⁺ T cell exhaustion in the tumor microenvironment. Cell Metab. 2019;30:143–56.E5. [DOI] [PubMed] [PMC]

75.

Timilshina M, You Z, Lacher SM, Acharya S, Jiang L, Kang Y, et al. Activation of mevalonate pathway via LKB1 is essential for stability of T_reg cells. Cell Rep. 2019;27:2948–61.E7. [DOI] [PubMed]

76.

Chen IC, Chang YC, Lu YS, Chung KP, Huang CS, Lu TP, et al. Clinical relevance of liver kinase B1(LKB1) protein and gene expression in breast cancer. Sci Rep. 2016;6:21374. [DOI] [PubMed] [PMC]

77.

Tan X, Liao Z, Liang H, Chen X, Zhang B, Chu L. Upregulation of liver kinase B1 predicts poor prognosis in hepatocellular carcinoma. Int J Oncol. 2018;53:1913–26. [DOI] [PubMed] [PMC]

78.

Zubiete-Franco I, García-Rodríguez JL, Lopitz-Otsoa F, Serrano-Macia M, Simon J, Fernández-Tussy P, et al. SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer. EBioMedicine. 2019;40:406–21. [DOI] [PubMed] [PMC]

79.

Finn RS, Cheng AL. Atezolizumab and bevacizumab in hepatocellular carcinoma. Reply. N Engl J Med. 2020;383:693–5. [DOI]

80.

Thrift AP, Natarajan Y, Liu Y, El-Serag HB. Statin use after diagnosis of hepatocellular carcinoma is associated with decreased mortality. Clin Gastroenterol Hepatol. 2019;17:2117–25.E3. [DOI] [PubMed] [PMC]

81.

Omori M, Okuma Y, Hakozaki T, Hosomi Y. Statins improve survival in patients previously treated with nivolumab for advanced non-small cell lung cancer: an observational study. Mol Clin Oncol. 2019;10:137–43. [DOI] [PubMed] [PMC]

82.

Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16:508–19. [DOI] [PubMed]

83.

Simon TG, Duberg AS, Aleman S, Hagstrom H, Nguyen LH, Khalili H, et al. Lipophilic statins and risk for hepatocellular carcinoma and death in patients with chronic viral hepatitis: results from a nationwide Swedish population. Ann Int Med. 2019;171:318–27. [DOI] [PubMed] [PMC]

84.

Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, et al. Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis. Cancers (Basel). 2020;12:874. [DOI] [PubMed] [PMC]

85.

Cao Z, Fan-Minogue H, Bellovin DI, Yevtodiyenko A, Arzeno J, Yang Q, et al. MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. Cancer Res. 2011;71:2286–97. [DOI] [PubMed] [PMC]

86.

Feng J, Dai W, Mao Y, Wu L, Li J, Chen K, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. J Exp Clin Cancer Res. 2020;39:24. [DOI] [PubMed] [PMC]

87.

Pinyopornpanish K, Al-Yaman W, Butler RS, Carey W, McCullough A, Romero-Marrero C. Chemopreventive effect of statin on hepatocellular carcinoma in patients with nonalcoholic steatohepatitis cirrhosis. Am J Gastroenterol. 2021;116:2258–69. [DOI] [PubMed]

88.

Lee JI, Lee HW, Lee KS, Lee HS, Park JY. Effects of statin use on the development and progression of nonalcoholic fatty liver disease: a nationwide nested case-control study. Am J Gastroenterol. 2021;116:116–24. [DOI] [PubMed]

89.

Pastori D, Polimeni L, Baratta F, Pani A, Del Ben M, Angelico F. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis. 2015;47:4–11. [DOI] [PubMed]

90.

Mira E, Carmona-Rodríguez L, Tardáguila M, Azcoitia I, González-Martín A, Almonacid L, et al. A lovastatin-elicited genetic program inhibits M2 macrophage polarization and enhances T cell infiltration into spontaneous mouse mammary tumors. Oncotarget. 2013;4:2288–301. [DOI] [PubMed] [PMC]

91.

Al Dujaily E, Baena J, Das M, Sereno M, Smith C, Kamata T, et al. Reduced protumorigenic tumor-associated macrophages with statin use in premalignant human lung adenocarcinoma. JNCI Cancer Spectr. 2020;4:pkz101. [DOI] [PubMed] [PMC]

92.

Takei A, Nagashima S, Takei S, Yamamuro D, Murakami A, Wakabayashi T, et al. Myeloid HMG-CoA reductase determines adipose tissue inflammation, insulin resistance, and hepatic steatosis in diet-induced obese mice. Diabetes. 2020;69:158–64. [DOI] [PubMed]

93.

Wang J, Tokoro T, Higa S, Kitajima I. Anti-inflammatory effect of pitavastatin on NF-κB activated by TNF-α in hepatocellular carcinoma cells. Biol Pharm Bull. 2006;29:634–9. [DOI] [PubMed]

94.

Shwe TH, Pothacharoen P, Phitak T, Wudtiwai B, Kongtawelert P. Atorvastatin attenuates programmed death ligand-1 (PD-L1) induction in human hepatocellular carcinoma cells. Int J Mol Sci. 2021;22:8755. [DOI] [PubMed] [PMC]