REFERENCES
1. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022;400:1345-62.
2. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.
3. El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389:2492-502.
4. Greten TF, Villanueva A, Korangy F, et al. Biomarkers for immunotherapy of hepatocellular carcinoma. Nat Rev Clin Oncol. 2023;20:780-98.
5. Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19:151-72.
6. Finn RS, Qin S, Ikeda M, et al.; IMbrave150 Investigators. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382:1894-905.
7. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.
8. Yau T, Galle PR, Decaens T, et al.; CheckMate 9DW investigators. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. Lancet. 2025;405:1851-64.
9. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20:651-68.
10. Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014;20:5064-74.
11. Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.
12. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-39.
13. Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819-29.
14. Pinter M, Jain RK, Duda DG. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 2021;7:113-23.
15. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91-7.
16. Björk JR, Bolte LA, Maltez Thomas A, et al. Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma. Nat Med. 2024;30:785-96.
17. Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602-9.
18. Routy B, Lenehan JG, Miller WH Jr, et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat Med. 2023;29:2121-32.
19. Hsu CL, Schnabl B. The gut-liver axis and gut microbiota in health and liver disease. Nat Rev Microbiol. 2023;21:719-33.
20. Hooper LV, Midtvedt T, Gordon JI. How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu Rev Nutr. 2002;22:283-307.
21. Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol. 2021;19:55-71.
22. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451-5.
23. Schulthess J, Pandey S, Capitani M, et al. The short chain fatty acid butyrate imprints an antimicrobial program in macrophages. Immunity. 2019;50:432-45.e7.
24. Sorrentino G, Perino A, Yildiz E, et al. Bile acids signal via TGR5 to activate intestinal stem cells and epithelial regeneration. Gastroenterology. 2020;159:956-68.e8.
25. Paik D, Yao L, Zhang Y, et al. Human gut bacteria produce ΤΗ17-modulating bile acid metabolites. Nature. 2022;603:907-12.
26. Zhao R, Fajardo J, Shen GX. Influence of northern wild rice on gut dysbiosis and short chain fatty acids: correlation with metabolic and inflammatory markers in mice on high fat diet. Nutrients. 2024;16:2834.
27. Wang X, Fang Y, Liang W, et al. Gut-liver translocation of pathogen Klebsiella pneumoniae promotes hepatocellular carcinoma in mice. Nat Microbiol. 2025;10:169-84.
28. Ma L, Li H, Hu J, et al. Indole alleviates diet-induced hepatic steatosis and inflammation in a manner involving myeloid cell 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Hepatology. 2020;72:1191-203.
29. Beaumont M, Neyrinck AM, Olivares M, et al. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J. 2018;32:fj201800544.
30. Roderburg C, Luedde T. The role of the gut microbiome in the development and progression of liver cirrhosis and hepatocellular carcinoma. Gut Microbes. 2014;5:441-5.
31. 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.
32. Refolo MG, Messa C, Guerra V, Carr BI, D’Alessandro R. Inflammatory mechanisms of HCC development. Cancers. 2020;12:641.
33. Aron-Wisnewsky J, Vigliotti C, Witjes J, et al. Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders. Nat Rev Gastroenterol Hepatol. 2020;17:279-97.
34. Duan Y, Llorente C, Lang S, et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature. 2019;575:505-11.
35. Grander C, Adolph TE, Wieser V, et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. 2018;67:891-901.
36. Ohtani N, Hara E. Gut-liver axis-mediated mechanism of liver cancer: a special focus on the role of gut microbiota. Cancer Sci. 2021;112:4433-43.
37. Bauer TM, Schwacha H, Steinbrückner B, et al. Small intestinal bacterial overgrowth in human cirrhosis is associated with systemic endotoxemia. Am J Gastroenterol. 2002;97:2364-70.
38. Song X, Sun X, Oh SF, et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature. 2020;577:410-5.
39. Ren Z, Li A, Jiang J, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut. 2019;68:1014-23.
40. Zheng R, Wang G, Pang Z, et al. Liver cirrhosis contributes to the disorder of gut microbiota in patients with hepatocellular carcinoma. Cancer Med. 2020;9:4232-50.
41. Tilg H, Adolph TE, Trauner M. Gut-liver axis: pathophysiological concepts and clinical implications. Cell Metab. 2022;34:1700-18.
42. 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.
43. 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.
44. 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.
45. 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.
46. Zhang C, Wang J, Sun Z, Cao Y, Mu Z, Ji X. Commensal microbiota contributes to predicting the response to immune checkpoint inhibitors in non-small-cell lung cancer patients. Cancer Sci. 2021;112:3005-17.
47. 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.
48. 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.
49. Thomas C, Pellicciari R, Pruzanski M, Auwerx J, Schoonjans K. Targeting bile-acid signalling for metabolic diseases. Nat Rev Drug Discov. 2008;7:678-93.
50. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016;7:189-200.
51. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res. 2013;54:2325-40.
52. Lee PC, Wu CJ, Hung YW, et al. Distinct gut microbiota but common metabolomic signatures between viral and MASLD HCC contribute to outcomes of combination immunotherapy. Hepatology. 2025;Epub ahead of print.
53. Choudhry H. The microbiome and its implications in cancer immunotherapy. Molecules. 2021;26:206.
55. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29-39.
56. Dai S, Chen Y, Cai W, et al. Combination immunotherapy in hepatocellular carcinoma: synergies among immune checkpoints, TKIs, and chemotherapy. J Hematol Oncol. 2025;18:85.
57. Ma H, Yang L, Liang Y, et al. B. thetaiotaomicron-derived acetic acid modulate immune microenvironment and tumor growth in hepatocellular carcinoma. Gut Microbes. 2024;16:2297846.
58. Hu C, Xu B, Wang X, et al. Gut microbiota-derived short-chain fatty acids regulate group 3 innate lymphoid cells in HCC. Hepatology. 2023;77:48-64.
59. 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.
60. Waldecker M, Kautenburger T, Daumann H, Busch C, Schrenk D. Inhibition of histone-deacetylase activity by short-chain fatty acids and some polyphenol metabolites formed in the colon. J Nutr Biochem. 2008;19:587-93.
61. Park J, Kim M, Kang SG, et al. Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR-S6K pathway. Mucosal Immunol. 2015;8:80-93.
62. Smith PM, Howitt MR, Panikov N, et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569-73.
63. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446-50.
64. Xia JK, Tang N, Wu XY, Ren HZ. Deregulated bile acids may drive hepatocellular carcinoma metastasis by inducing an immunosuppressive microenvironment. Front Oncol. 2022;12:1033145.
65. Sun R, Zhang Z, Bao R, et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis. J Hepatol. 2022;77:453-66.
66. Nie Q, Luo X, Wang K, et al. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway. Cell. 2024;187:2717-34.e33.
67. Petty AJ, Owen DH, Yang Y, Huang X. Targeting tumor-associated macrophages in cancer immunotherapy. Cancers. 2021;13:5318.
68. Retracted: M2 macrophage-derived exosomes facilitate HCC metastasis by transferring αMβ2 integrin to tumor cells. Hepatology. 2021;74:3564.
69. Miyamoto Y, Kikuta J, Matsui T, et al. Periportal macrophages protect against commensal-driven liver inflammation. Nature. 2024;629:901-9.
70. Li W, Hang S, Fang Y, et al. A bacterial bile acid metabolite modulates T(reg) activity through the nuclear hormone receptor NR4A1. Cell Host Microbe. 2021;29:1366-77.e9.
71. Koenis DS, Medzikovic L, van Loenen PB, et al. Nuclear receptor Nur77 limits the macrophage inflammatory response through transcriptional reprogramming of mitochondrial metabolism. Cell Rep. 2018;24:2127-40.e7.
72. Zhao CN, Li SS, Yau T, et al. Phocaeicola vulgatus induces immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production. Cell Rep Med. 2025;6:102370.
73. Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9:3294.
74. Renga G, Nunzi E, Pariano M, et al. Optimizing therapeutic outcomes of immune checkpoint blockade by a microbial tryptophan metabolite. J Immunother Cancer. 2022;10:e003725.
75. Zelante T, Iannitti RG, Cunha C, et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372-85.
76. Kjer-Nielsen L, Patel O, Corbett AJ, et al. MR1 presents microbial vitamin B metabolites to MAIT cells. Nature. 2012;491:717-23.
77. Legoux F, Salou M, Lantz O. MAIT cell development and functions: the microbial connection. Immunity. 2020;53:710-23.
78. Toubal A, Nel I, Lotersztajn S, Lehuen A. Mucosal-associated invariant T cells and disease. Nat Rev Immunol. 2019;19:643-57.
79. Duan M, Goswami S, Shi JY, et al. Activated and exhausted MAIT cells foster disease progression and indicate poor outcome in hepatocellular carcinoma. Clin Cancer Res. 2019;25:3304-16.
80. Ruf B, Catania VV, Wabitsch S, et al. Activating mucosal-associated invariant T cells induces a broad antitumor response. Cancer Immunol Res. 2021;9:1024-34.
81. Gäbele E, Dostert K, Hofmann C, et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol. 2011;55:1391-9.
82. Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol. 2015;12:387-400.
83. Jing YY, Han ZP, Sun K, et al. Toll-like receptor 4 signaling promotes epithelial-mesenchymal transition in human hepatocellular carcinoma induced by lipopolysaccharide. BMC Med. 2012;10:98.
84. Zhang Y, Liu W, Wong CC, et al. Catenibacteriummitsuokai promotes hepatocellular carcinogenesis by binding to hepatocytes and generating quinolinic acid. Cell Metab. 2025;37:1998-2013.e7.
85. Porcari S, Benech N, Valles-Colomer M, et al. Key determinants of success in fecal microbiota transplantation: from microbiome to clinic. Cell Host Microbe. 2023;31:712-33.
86. 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.
87. 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.
88. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559-63.
89. Falony G, Joossens M, Vieira-Silva S, et al. Population-level analysis of gut microbiome variation. Science. 2016;352:560-4.
90. Singh V, Yeoh BS, Chassaing B, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 2018;175:679-94.e22.
91. Woolf EC, Syed N, Scheck AC. Tumor metabolism, the ketogenic diet and β-hydroxybutyrate: novel approaches to adjuvant brain tumor therapy. Front Mol Neurosci. 2016;9:122.
92. Wang YH, Liu CL, Chiu WC, Twu YC, Liao YJ. HMGCS2 mediates ketone production and regulates the proliferation and metastasis of hepatocellular carcinoma. Cancers. 2019;11:1876.
93. Cheng K, Cai N, Yang X, et al. Short-term starvation boosts anti-PD-L1 therapy by reshaping tumor-associated macrophages in hepatocellular carcinoma. Hepatology. 2025;82:1414-31.
94. 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.
95. Fessas P, Naeem M, Pinter M, et al. Early antibiotic exposure is not detrimental to therapeutic effect from immunotherapy in hepatocellular carcinoma. Liver Cancer. 2021;10:583-92.
96. Pinato DJ, Li X, Mishra-Kalyani P, et al. Association between antibiotics and adverse oncological outcomes in patients receiving targeted or immune-based therapy for hepatocellular carcinoma. JHEP Rep. 2023;5:100747.
97. Maesaka K, Sakamori R, Yamada R, et al. Pretreatment with antibiotics is associated with reduced therapeutic response to atezolizumab plus bevacizumab in patients with hepatocellular carcinoma. PLoS One. 2023;18:e0281459.
98. Kaźmierczak-Siedlecka K, Skonieczna-Żydecka K, Hupp T, Duchnowska R, Marek-Trzonkowska N, Połom K. Next-generation probiotics - do they open new therapeutic strategies for cancer patients? Gut Microbes. 2022;14:2035659.
99. Lau HC, Zhang X, Ji F, et al. Lactobacillus acidophilus suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma through producing valeric acid. EBioMedicine. 2024;100:104952.
100. 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.
101. Yu J, Zhu P, Shi L, et al. Bifidobacterium longum promotes postoperative liver function recovery in patients with hepatocellular carcinoma. Cell Host Microbe. 2024;32:131-44.e6.
102. Tang L, Wang J, Lin N, et al. Immune checkpoint inhibitor-associated colitis: from mechanism to management. Front Immunol. 2021;12:800879.
103. Nenu I, Baldea I, Coadă CA, et al. Lactobacillus rhamnosus probiotic treatment modulates gut and liver inflammatory pathways in a hepatocellular carcinoma murine model. A preliminary study. Food Chem Toxicol. 2024;183:114314.
104. Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369:1481-9.
105. Lee KA, Thomas AM, Bolte LA, et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med. 2022;28:535-44.
106. Liu R, Zou Y, Wang WQ, et al. Gut microbial structural variation associates with immune checkpoint inhibitor response. Nat Commun. 2023;14:7421.
107. Piccinno G, Thompson KN, Manghi P, et al. Pooled analysis of 3,741 stool metagenomes from 18 cohorts for cross-stage and strain-level reproducible microbial biomarkers of colorectal cancer. Nat Med. 2025;31:2416-29.
108. Zhu X, Huang X, Hu M, et al. A specific enterotype derived from gut microbiome of older individuals enables favorable responses to immune checkpoint blockade therapy. Cell Host Microbe. 2024;32:489-505.e5.
109. Hu M, Zhu X, Huang X, et al. Optimizing anti-PD-1/PD-L1 therapy efficacy and fecal microbiota transplantation donor selection through gut mycobiome-based enterotype. Cell Rep. 2025;44:115589.
110. Derosa L, Iebba V, Silva CAC, et al. Custom scoring based on ecological topology of gut microbiota associated with cancer immunotherapy outcome. Cell. 2024;187:3373-89.e16.
111. 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.
112. Sterlin D, Fadlallah J, Slack E, Gorochov G. The antibody/microbiota interface in health and disease. Mucosal Immunol. 2020;13:3-11.
113. Larman HB, Zhao Z, Laserson U, et al. Autoantigen discovery with a synthetic human peptidome. Nat Biotechnol. 2011;29:535-41.
114. Vogl T, Klompus S, Leviatan S, et al. Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota. Nat Med. 2021;27:1442-50.
115. Li J, Ma Y, Cao Y, et al. Integrating microbial GWAS and single-cell transcriptomics reveals associations between host cell populations and the gut microbiome. Nat Microbiol. 2025;10:1210-26.
116. Wu G, Xu T, Zhao N, et al. A core microbiome signature as an indicator of health. Cell. 2024;187:6550-65.e11.
117. Marcella C, Cui B, Kelly CR, Ianiro G, Cammarota G, Zhang F. Systematic review: the global incidence of faecal microbiota transplantation-related adverse events from 2000 to 2020. Aliment Pharmacol Ther. 2021;53:33-42.
118. Drewes JL, Corona A, Sanchez U, et al. Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficile. JCI Insight. 2019;4:130848.
119. Porcari S, Ciccarese C, Heidrich V, et al. Fecal microbiota transplantation plus pembrolizumab and axitinib in metastatic renal cell carcinoma: the randomized phase 2 TACITO trial. Nat Med. 2026;32:1316-24.
120. Fernandes R, Jabbarizadeh B, Rajeh A, et al. Fecal microbiota transplantation plus immunotherapy in metastatic renal cell carcinoma: the phase 1 PERFORM trial. Nat Med. 2026;32:1325-36.
121. Duttagupta S, Messaoudene M, Hunter S, et al. Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial. Nat Med. 2026;32:1337-50.
122. Haifer C, Paramsothy S, Kaakoush NO, et al. Lyophilised oral faecal microbiota transplantation for ulcerative colitis (LOTUS): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2022;7:141-51.
