REFERENCES
1. Sung H, Ferlay J, Siegel RL, 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.
2. 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.
3. Rinella ME, Lazarus JV, Ratziu V, et al; NAFLD Nomenclature consensus group. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542-56.
4. Zhou J, Sun H, Wang Z, et al. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition). Liver Cancer. 2023;12:405-44.
5. Singal AG, Llovet JM, Yarchoan M, et al. AASLD practice guidance on prevention, diagnosis, and treatment of hepatocellular carcinoma. Hepatology. 2023;78:1922-65.
6. Llovet JM, Pinyol R, Kelley RK, et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat Cancer. 2022;3:386-401.
7. Lazzaro A, Hartshorn KL. A comprehensive narrative review on the history, current landscape, and future directions of hepatocellular carcinoma (HCC) systemic therapy. Cancers. 2023;15:2506.
8. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16:563-80.
9. Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021;18:525-43.
10. Kim CG, Kim C, Yoon SE, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021;74:350-9.
11. Yamaguchi H, Hsu JM, Sun L, Wang SC, Hung MC. Advances and prospects of biomarkers for immune checkpoint inhibitors. Cell Rep Med. 2024;5:101621.
12. Ha S, Wong VW, Zhang X, Yu J. Interplay between gut microbiome, host genetic and epigenetic modifications in MASLD and MASLD-related hepatocellular carcinoma. Gut. 2024;74:141-52.
13. Schwabe RF, Greten TF. Gut microbiome in HCC - mechanisms, diagnosis and therapy. J Hepatol. 2020;72:230-8.
14. Mao J, Wang D, Long J, et al. Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers. J Immunother Cancer. 2021;9:e003334.
15. Lee PC, Wu CJ, Hung YW, et al. Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma. J Immunother Cancer. 2022;10:e004779.
16. Zhang C, Liu H, Sun L, et al. An overview of host-derived molecules that interact with gut microbiota. Imeta. 2023;2:e88.
17. Martinez-Guryn K, Leone V, Chang EB. Regional diversity of the gastrointestinal microbiome. Cell Host Microbe. 2019;26:314-24.
18. Shui L, Yang X, Li J, Yi C, Sun Q, Zhu H. Gut microbiome as a potential factor for modulating resistance to cancer immunotherapy. Front Immunol. 2019;10:2989.
19. Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer. 2019;7:193.
20. Chung MW, Kim MJ, Won EJ, et al. Gut microbiome composition can predict the response to nivolumab in advanced hepatocellular carcinoma patients. World J Gastroenterol. 2021;27:7340-9.
21. Yau T, Park JW, Finn RS, et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2022;23:77-90.
22. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.
23. Yu H, Lin G, Jiang J, et al. Synergistic activity of Enterococcus Faecium-induced ferroptosis via expansion of IFN-γ+CD8+ T cell population in advanced hepatocellular carcinoma treated with sorafenib. Gut Microbes. 2024;16:2410474.
24. Chai X, Tang Y, Li X, et al. Lenvatinib improves the relative abundance of probiotics in intestinal flora of patients with primary liver cancer. Research Square. 2024;Research Square:rs-4024621. Available from https://doi.org/10.21203/rs.3.rs-4024621/v1 [accessed 28 May 2025].
25. Simpson RC, Shanahan ER, Scolyer RA, Long GV. Towards modulating the gut microbiota to enhance the efficacy of immune-checkpoint inhibitors. Nat Rev Clin Oncol. 2023;20:697-715.
26. Wu H, Zheng X, Pan T, et al. Dynamic microbiome and metabolome analyses reveal the interaction between gut microbiota and anti-PD-1 based immunotherapy in hepatocellular carcinoma. Int J Cancer. 2022;151:1321-34.
27. Lu Y, Yuan X, Wang M, et al. Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies. J Hematol Oncol. 2022;15:47.
28. Xin Y, Peng G, Song W, Zhou X, Huang X, Cao X. Gut microbiota as a prognostic biomarker for unresectable hepatocellular carcinoma treated with anti-PD-1 therapy. Front Genet. 2024;15:1366131.
29. Shen YC, Lee PC, Kuo YL, et al. An exploratory study for the association of gut microbiome with efficacy of immune checkpoint inhibitor in patients with hepatocellular carcinoma. J Hepatocell Carcinoma. 2021;8:809-22.
30. Cai X, Cho JY, Chen L, et al. Enriched pathways in gut microbiome predict response to immune checkpoint inhibitor treatment across demographic regions and various cancer types. iScience. 2025;28:112162.
31. Cheung KS, Lam LK, Seto WK, Leung WK. Use of antibiotics during immune checkpoint inhibitor treatment is associated with lower survival in hepatocellular carcinoma. Liver Cancer. 2021;10:606-14.
32. Alshammari K, Alsugheir F, Aldawoud M, et al. Association between antibiotic exposure and survival in patients with hepatocellular carcinoma treated with nivolumab. J Clin Oncol. 2021;39:e16186.
33. Spahn S, Roessler D, Pompilia R, et al. Clinical and genetic tumor characteristics of responding and non-responding patients to PD-1 inhibition in hepatocellular carcinoma. Cancers. 2020;12:3830.
34. Torres MDT, Brooks EF, Cesaro A, et al. Mining human microbiomes reveals an untapped source of peptide antibiotics. Cell. 2024;187:5453-67.e15.
35. Pierrard J, Seront E. Impact of the gut microbiome on immune checkpoint inhibitor efficacy - a systematic review. Curr Oncol. 2019;26:395-403.
36. Pinato DJ, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. 2019;5:1774-8.
37. Ramirez J, Guarner F, Bustos Fernandez L, Maruy A, Sdepanian VL, Cohen H. Antibiotics as major disruptors of gut microbiota. Front Cell Infect Microbiol. 2020;10:572912.
38. Zhang W, Zhang Y, Li Y, Ma D, Zhang H, Kwok LY.
39. ClinicalTrials.gov. Qiang Xu, Jiangxi Provincial Cancer Hospital. Available from https://classic.clinicaltrials.gov/ct2/show/NCT05032014 [accessed 28 May 2025].
40. Huang L, Duan C, Zhao Y, et al. Reduction of aflatoxin B1 toxicity by lactobacillus plantarum C88: a potential probiotic strain isolated from Chinese traditional fermented food “tofu”. PLoS One. 2017;12:e0170109.
41. Russo E, Fiorindi C, Giudici F, Amedei A. Immunomodulation by probiotics and prebiotics in hepatocellular carcinoma. World J Hepatol. 2022;14:372-85.
42. Heydari Z, Rahaie M, Alizadeh AM, Agah S, Khalighfard S, Bahmani S. Effects of Lactobacillus acidophilus and Bifidobacterium bifidum probiotics on the expression of MicroRNAs 135b, 26b, 18a and 155, and their involving genes in mice colon cancer. Probiotics Antimicrob Proteins. 2019;11:1155-62.
43. Elshaer AM, El-Kharashi OA, Hamam GG, Nabih ES, Magdy YM, Abd El Samad AA. Involvement of TLR4/CXCL9/PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats. Tissue Cell. 2019;60:38-47.
44. Wilson B, Whelan K. Prebiotic inulin-type fructans and galacto-oligosaccharides: definition, specificity, function, and application in gastrointestinal disorders. J Gastroenterol Hepatol. 2017;32 Suppl 1:64-8.
45. Hutkins R, Walter J, Gibson GR, et al. Classifying compounds as prebiotics - scientific perspectives and recommendations. Nat Rev Gastroenterol Hepatol. 2025;22:54-70.
46. Liu Y, Wang J, Wu C. Modulation of gut microbiota and immune system by probiotics, pre-biotics, and post-biotics. Front Nutr. 2022;8:634897.
47. Meyers G, Samouda H, Bohn T. Short chain fatty acid metabolism in relation to gut microbiota and genetic variability. Nutrients. 2022;14:5361.
48. Hao Y, Hao Z, Zeng X, Lin Y. Gut microbiota and metabolites of cirrhotic portal hypertension: a novel target on the therapeutic regulation. J Gastroenterol. 2024;59:788-97.
49. Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369:1481-9.
50. Ashaolu TJ, Ashaolu JO, Adeyeye SAO. Fermentation of prebiotics by human colonic microbiota in vitro and short-chain fatty acids production: a critical review. J Appl Microbiol. 2021;130:677-87.
51. Kim K, Kwon O, Ryu TY, et al. Propionate of a microbiota metabolite induces cell apoptosis and cell cycle arrest in lung cancer. Mol Med Rep. 2019;20:1569-74.
52. Teyani R, Moniri NH. Gut feelings in the islets: the role of the gut microbiome and the FFA2 and FFA3 receptors for short chain fatty acids on β-cell function and metabolic regulation. Br J Pharmacol. 2023;180:3113-29.
53. Cornide-Petronio ME, Álvarez-Mercado AI, Jiménez-Castro MB, Peralta C. Current knowledge about the effect of nutritional status, supplemented nutrition diet, and gut microbiota on hepatic ischemia-reperfusion and regeneration in liver surgery. Nutrients. 2020;12:284.
54. Li X, Zhang S, Guo G, Han J, Yu J. Gut microbiome in modulating immune checkpoint inhibitors. EBioMedicine. 2022;82:104163.
55. Kim Y, Kim G, Kim S, et al. Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. Cell Host Microbe. 2024;32:1380-93.e9.
56. Pomej K, Frick A, Scheiner B, et al. Study protocol: fecal microbiota transplant combined with atezolizumab/bevacizumab in patients with hepatocellular carcinoma who failed to achieve or maintain objective response to atezolizumab/bevacizumab - the FAB-HCC pilot study. PLoS One. 2025;20:e0321189.
57. Xiao K, Li K, Xiao K, Yang J, Zhou L. Gut microbiota and hepatocellular carcinoma: metabolic products and immunotherapy modulation. Cancer Med. 2025;14:e70914.
58. Cigliano A, Liao W, Deiana GA, Rizzo D, Chen X, Calvisi DF. Preclinical models of hepatocellular carcinoma: current utility, limitations, and challenges. Biomedicines. 2024;12:1624.
59. Jugder BE, Kamareddine L, Watnick PI. Microbiota-derived acetate activates intestinal innate immunity via the Tip60 histone acetyltransferase complex. Immunity. 2021;54:1683-97.e3.
60. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30:492-506.
61. He Y, Fu L, Li Y, et al. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell Metab. 2021;33:988-1000.e7.
62. Microbiota-induced IFN-I signaling promotes an antitumor microenvironment. Cancer Discov. 2021;11:2955.
64. Liu X, Li S, Wang L, Ma K. Microecological regulation in HCC therapy: gut microbiome enhances ICI treatment. Biochim Biophys Acta Mol Basis Dis. 2024;1870:167230.
65. Araji G, Maamari J, Ahmad FA, Zareef R, Chaftari P, Yeung SJ. The emerging role of the gut microbiome in the cancer response to immune checkpoint inhibitors: a narrative review. J Immunother Precis Oncol. 2022;5:13-25.
66. Peng Z, Cheng S, Kou Y, et al. The gut microbiome is associated with clinical response to anti-PD-1/PD-L1 immunotherapy in gastrointestinal cancer. Cancer Immunol Res. 2020;8:1251-61.
67. Davar D, Dzutsev AK, McCulloch JA, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595-602.
68. Jin Y, Dong H, Xia L, et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC. J Thorac Oncol. 2019;14:1378-89.
69. Rizvi ZA, Dalal R, Sadhu S, et al. High-salt diet mediates interplay between NK cells and gut microbiota to induce potent tumor immunity. Sci Adv. 2021;7:eabg5016.
70. Si W, Liang H, Bugno J, et al.
71. Lam KC, Araya RE, Huang A, et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. 2021;184:5338-56.e21.
72. Wu XQ, Ying F, Chung KPS, et al. Intestinal Akkermansia muciniphila complements the efficacy of PD1 therapy in MAFLD-related hepatocellular carcinoma. Cell Rep Med. 2025;6:101900.
73. Zhang L, Jiang L, Yu L, et al. Inhibition of UBA6 by inosine augments tumour immunogenicity and responses. Nat Commun. 2022;13:5413.
74. Bell HN, Rebernick RJ, Goyert J, et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell. 2022;40:185-200.e6.
75. Ma J, Li J, Jin C, et al. Association of gut microbiome and primary liver cancer: a two-sample Mendelian randomization and case-control study. Liver Int. 2023;43:221-33.
76. Liu X, Li S, Wang L, Ma K. Microecological regulation in HCC therapy: gut microbiome enhances ICI treatment. Biochim Biophys Acta Mol Basis Dis. ;1870:167230.
77. Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21:719-33.
78. Tilg H, Adolph TE, Trauner M. Gut-liver axis: pathophysiological concepts and clinical implications. Cell Metab. 2022;34:1700-18.
79. Zheng Z, Wang B. The gut-liver axis in health and disease: the role of gut microbiota-derived signals in liver injury and regeneration. Front Immunol. 2021;12:775526.
80. Lee J, d’Aigle J, Atadja L, et al. Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res. 2020;127:453-65.
81. Song Y, Lau HC, Zhang X, Yu J. Bile acids, gut microbiota, and therapeutic insights in hepatocellular carcinoma. Cancer Biol Med. 2023;21:144-62.
82. Zhang X, Coker OO, Chu ES, et al. Dietary cholesterol drives fatty liver-associated liver cancer by modulating gut microbiota and metabolites. Gut. 2021;70:761-74.
83. Lynch L, Nowak M, Varghese B, et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity. 2012;37:574-87.
84. Behary J, Amorim N, Jiang XT, et al. Gut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma. Nat Commun. 2021;12:187.
85. Huang H, Ren Z, Gao X, 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.
86. Zhou J, Tripathi M, Sinha RA, Singh BK, Yen PM. Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease. Hepatoma Res. 2021;7:11.
87. 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.
88. Zhou A, Tang L, Zeng S, Lei Y, Yang S, Tang B. Gut microbiota: a new piece in understanding hepatocarcinogenesis. Cancer Lett. 2020;474:15-22.
89. Laface C, Lauricella E, Ranieri G, et al. HCC and immunotherapy: the potential predictive role of gut microbiota and future therapeutic strategies. Onco. 2025;5:9.
90. Monti E, Vianello C, Leoni I, et al. Gut microbiome modulation in hepatocellular carcinoma: preventive role in NAFLD/NASH progression and potential applications in immunotherapy-based strategies. Cells. 2025;14:84.
91. Murai H, Kodama T, Maesaka K, et al. Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma. Hepatology. 2023;77:77-91.
92. Chen K, Shuen TWH, Chow PKH. The association between tumour heterogeneity and immune evasion mechanisms in hepatocellular carcinoma and its clinical implications. Br J Cancer. 2024;131:420-9.
93. Suthen S, Lim CJ, Nguyen PHD, et al. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022;76:1329-44.
94. Pral LP, Fachi JL, Corrêa RO, Colonna M, Vinolo MAR. Hypoxia and HIF-1 as key regulators of gut microbiota and host interactions. Trends Immunol. 2021;42:604-21.
95. Berndt N, Eckstein J, Heucke N, et al. Metabolic heterogeneity of human hepatocellular carcinoma: implications for personalized pharmacological treatment. FEBS J. 2021;288:2332-46.