REFERENCES
1. Liu Y, Liu L. Changes in the epidemiology of hepatocellular carcinoma in Asia. Cancers. 2022;14:4473.
2. 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.
3. Abboud Y, Ismail M, Khan H, et al. Hepatocellular carcinoma incidence and mortality in the usa by sex, age, and race: a nationwide analysis of two decades. J Clin Transl Hepatol. 2024;12:172-81.
4. Chon YE, Lee J, Yoon EL, et al. Changes in antiviral treatment rate for hepatitis B virus before hepatocellular carcinoma diagnosis: a nationwide Korean study. Eur J Gastroenterol Hepatol. 2025;37:1166-72.
5. Facciorusso A, Tartaglia N, Villani R, et al. Lenvatinib versus sorafenib as first-line therapy of advanced hepatocellular carcinoma: a systematic review and meta-analysis. Am J Transl Res. 2021;13:2379-87.
6. Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391:1163-73.
7. Llovet JM, Ricci S, Mazzaferro V, et al. ; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-90.
8. Zhu AX, Finn RS, Edeline J, et al. ; KEYNOTE-224 investigators. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19:940-52.
9. 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.
10. 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.
11. Rimassa L, Chan SL, Sangro B, et al. Five-year overall survival update from the HIMALAYA study of tremelimumab plus durvalumab in unresectable HCC. J Hepatol. 2025;83:899-908.
12. Abou-alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1:EVIDoa2100070.
13. 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.
14. Ren Z, Xu J, Bai Y, et al. ; ORIENT-32 study group. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol. 2021;22:977-90.
15. Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6.
16. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168:707-23.
17. Sia D, Jiao Y, Martinez-Quetglas I, et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology. 2017;153:812-26.
18. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231-5.
19. Luke JJ, Bao R, Sweis RF, Spranger S, Gajewski TF. WNT/β-catenin pathway activation correlates with immune exclusion across human cancers. Clin Cancer Res. 2019;25:3074-83.
20. Gettinger S, Choi J, Hastings K, et al. Impaired HLA Class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 2017;7:1420-35.
21. Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.
23. De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457-74.
24. 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.
25. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544-8.
26. Lu Y, Yang A, Quan C, et al. A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma. Nat Commun. 2022;13:4594.
27. Zheng Y, Wang T, Tu X, et al. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunotherapy Cancer. 2019;7:193.
28. 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.
29. Dizman N, Meza L, Bergerot P, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022;28:704-12.
30. Mager LF, Burkhard R, Pett N, et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369:1481-9.
31. Baruch EN, Youngster I, Ben-Betzalel G, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602-9.
32. Smith M, Dai A, Ghilardi G, et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat Med. 2022;28:713-23.
33. Bian CF, Wang Y, Yu A, et al. Gut microbiota changes and biological mechanism in hepatocellular carcinoma after transarterial chemoembolization treatment. Front Oncol. 2022;12:1002589.
34. Chowdhury S, Castro S, Coker C, Hinchliffe TE, Arpaia N, Danino T. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med. 2019;25:1057-63.
35. Finn RS, Ryoo BY, Merle P, et al. ; KEYNOTE-240 investigators. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, Phase III trial. J Clin Oncol. 2020;38:193-202.
36. Zhang L, Chen C, Chai D, et al. The association between antibiotic use and outcomes of HCC patients treated with immune checkpoint inhibitors. Front Immunol. 2022;13:956533.
37. Wang Z, Wang Y, Gao P, Ding J. Immune checkpoint inhibitor resistance in hepatocellular carcinoma. Cancer Lett. 2023;555:216038.
38. Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021;592:450-6.
39. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325-40.
40. 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.
41. 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.
42. Gilbert JA, Blaser MJ, Caporaso JG, Jansson JK, Lynch SV, Knight R. Current understanding of the human microbiome. Nat Med. 2018;24:392-400.
43. Tripathi A, Debelius J, Brenner DA, et al. The gut-liver axis and the intersection with the microbiome. Nat Rev Gastroenterol Hepatol. 2018;15:397-411.
44. Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut. J Physiol. 2012;590:447-58.
46. Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver disease: Pathophysiological basis for therapy. J Hepatol. 2020;72:558-77.
47. Szabo G, Petrasek J. Inflammasome activation and function in liver disease. Nat Rev Gastroenterol Hepatol. 2015;12:387-400.
48. Jia W, Xie G, Jia W. Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nat Rev Gastroenterol Hepatol. 2018;15:111-28.
49. Chiang JYL, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am J Physiol Gastrointest Liver Physiol. 2020;318:G554-73.
50. Tilg H, Adolph TE, Trauner M. Gut-liver axis: Pathophysiological concepts and clinical implications. Cell Metab. 2022;34:1700-18.
51. Wahlström A, Sayin SI, Marschall HU, Bäckhed F. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab. 2016;24:41-50.
52. Juneja P, Tripathi DM, Kaur S. Revisiting the gut-liver axis: gut lymphatic system in liver cirrhosis and portal hypertension. Am J Physiol Gastrointest Liver Physiol. 2022;322:G473-9.
53. Yang X, Lu D, Zhuo J, Lin Z, Yang M, Xu X. The gut-liver axis in immune remodeling: new insight into liver diseases. Int J Biol Sci. 2020;16:2357-66.
54. 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.
55. Chua HH, Chen YH, Wu LL, et al. Antagonism between gut Ruminococcus gnavus and Akkermansia muciniphila modulates the progression of chronic hepatitis B. Cell Mol Gastroenterol Hepatol. 2024;17:361-81.
56. Zhang N, Gou Y, Liang S, et al. Dysbiosis of gut microbiota promotes hepatocellular carcinoma progression by regulating the immune response. J Immunol Res. 2021;2021:4973589.
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. Yang J, Lim J, Kim EH, et al. Prognostic Role of Short-Chain Fatty Acid-Producing Gut Microbiota and Gut Microbial Dynamics in Patients with Hepatocellular Carcinoma Receiving Chemoembolization: A Prospective Study. J Hepatocell Carcinoma. 2025;12:1991-2004.
59. Mcculloch JA, Davar D, Rodrigues RR, et al. Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1. Nat Med. 2022;28:545-56.
60. Gong J, Chehrazi‐Raffle A, Placencio‐Hickok V, Guan M, Hendifar A, Salgia R. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin Transl Med. 2019;8:e9.
61. Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol. 2016;8:1354-69.
62. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier dysfunction, LPS translocation, and disease development. J Endocr Soc. 2020;4:bvz039.
63. Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science. 2021;371:eabc4552.
64. Yao J, Ning B, Ding J. The gut microbiota: an emerging modulator of drug resistance in hepatocellular carcinoma. Gut Microbes. 2025;17:2473504.
65. Choi YH, Yu AM. ABC transporters in multidrug resistance and pharmacokinetics, and strategies for drug development. Curr Pharm Des. 2014;20:793-807.
66. de Groot RA, Reedijk D, Faucher Q, Mihăilă SM, Masereeuw R. Strategies for overcoming ABC transporter-mediated multidrug resistance in colorectal cancer. Am J Physiol Cell Physiol. 2025;329:C699-717.
67. Wu D, Fan Y, Zhang M, et al. Tumor-suppressing multi-enterobacteria and PD-1/PD-L1 immune checkpoint inhibitor combination improves the outcome of hepatocellular carcinoma therapy. Front Immunol. 2025;16:1598436.
68. Lu Y, Yuan H, Liang S, et al. Microbial metabolite-driven immune reprogramming in tumor immunotherapy: mechanisms and therapeutic perspectives. Front Immunol. 2025;16:1603658.
69. Wang J, Hao Y, Yang Y, Zhang Y, Xu C, Yang R. Gut microbiota derived indole-3-acetic acid ameliorates precancerous inflammatory intestinal milieu to inhibit tumorigenesis through IL-35. J Immunother Cancer. 2025;13:e011155.
70. Jia B, Jeon CO. Promotion and induction of liver cancer by gut microbiome-mediated modulation of bile acids. PLoS Pathog. 2019;15:e1007954.
71. 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.
72. Donohoe DR, Collins LB, Wali A, Bigler R, Sun W, Bultman SJ. The warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation. Mol Cell. 2012;48:612-26.
73. Lai MW, Chu YD, Hsu CW, Chen YC, Liang KH, Yeh CT. Multi-omics analyses identify signatures in patients with liver cirrhosis and hepatocellular carcinoma. Cancers. 2022;15:210.
74. Yang Q, He Y, Tian L, et al. Anti-tumor effect of infant-derived Enterococcus via the inhibition of proliferation and inflammation as well as the promotion of apoptosis. Food Funct. 2023;14:2223-38.
75. Yang Y, Bo Z, Wang J, et al. Machine learning based on alcohol drinking-gut microbiota-liver axis in predicting the occurrence of early-stage hepatocellular carcinoma. BMC Cancer. 2024;24:1468.
76. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018;33:570-80.
77. Wang J, Xu W, Wang R, Cheng R, Tang Z, Zhang M. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct. 2021;12:3597-610.
78. Chelakkot C, Choi Y, Kim DK, et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Exp Mol Med. 2018;50:e450.
79. Depommier C, Everard A, Druart C, et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019;25:1096-103.
80. Hsieh CY, Osaka T, Moriyama E, Date Y, Kikuchi J, Tsuneda S. Strengthening of the intestinal epithelial tight junction by Bifidobacterium bifidum. Physiol Rep. 2015;3:e12327.
81. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020;30:492-506.
82. Horvath A, Leber B, Schmerboeck B, et al. Randomised clinical trial: the effects of a multispecies probiotic vs. placebo on innate immune function, bacterial translocation and gut permeability in patients with cirrhosis. Aliment Pharmacol Ther. 2016;44:926-35.
83. Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity. 2015;42:344-55.
84. 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.
85. Zhang M, Huang X, Zhang Y, et al. Gut microbial metabolite butyrate suppresses hepatocellular carcinoma growth via CXCL11-dependent enhancement of natural killer cell infiltration. Gut Microbes. 2025;17:2519706.
86. Arpaia N, Campbell C, Fan X, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451-5.
87. Sun M, Wu W, Chen L, et al. Microbiota-derived short-chain fatty acids promote Th1 cell IL-10 production to maintain intestinal homeostasis. Nat Commun. 2018;9:3555.
88. 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.
89. Singh N, Gurav A, Sivaprakasam S, et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity. 2014;40:128-39.
90. He J, Zhang P, Shen L, et al. Short-Chain fatty acids and their association with signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci. 2020;21:6356.
91. Chang PV, Hao L, Offermanns S, Medzhitov R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111:2247-52.
92. Nomura M, Nagatomo R, Doi K, et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw Open. 2020;3:e202895.
93. Parada Venegas D, De la Fuente MK, Landskron G, et al. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Front Immunol. 2019;10:277.
94. Nastasi C, Candela M, Bonefeld CM, et al. The effect of short-chain fatty acids on human monocyte-derived dendritic cells. Sci Rep. 2015;5:16148.
95. Ma C, Han M, Heinrich B, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360:eaan5931.
96. Yamada S, Takashina Y, Watanabe M, et al. Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice. Oncotarget. 2018;9:9925-39.
97. Sydor S, Best J, Messerschmidt I, et al. Altered microbiota diversity and bile acid signaling in cirrhotic and noncirrhotic NASH-HCC. Clin Transl Gastroenterol. 2020;11:e00131.
98. Petrick JL, Florio AA, Koshiol J, et al. Prediagnostic concentrations of circulating bile acids and hepatocellular carcinoma risk: REVEAL‐HBV and HCV studies. Int J Cancer. 2020;147:2743-53.
99. Thomas CE, Luu HN, Wang R, et al. Association between pre-diagnostic serum bile acids and hepatocellular carcinoma: The Singapore Chinese Health Study. Cancers. 2021;13:2648.
100. Colosimo S, Tomlinson JW. Bile acids as drivers and biomarkers of hepatocellular carcinoma. World J Hepatol. 2022;14:1730-8.
102. Yang Z, Zhou F, Zhan D, Li P, Pan J. Levels of bile acid metabolism are associated with alterations of gut microbes in hepatocellular carcinoma. Mol Carcinog. 2025;64:543-51.
103. Yang R, Qian L. Research on gut microbiota-derived secondary bile acids in cancer progression. Integr Cancer Ther. 2022;21:15347354221114100.
104. Shen R, Ke L, Li Q, et al. Abnormal bile acid-microbiota crosstalk promotes the development of hepatocellular carcinoma. Hepatol Int. 2022;16:396-411.
105. Song X, Sun X, Oh SF, et al. Microbial bile acid metabolites modulate gut RORγ+ regulatory T cell homeostasis. Nature. 2019;577:410-5.
106. Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9:3294.
107. Platten M, Nollen EAA, Röhrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019;18:379-401.
108. Luo W, Li R, Pan C, Luo C. Gut microbiota-derived metabolites in immunomodulation and gastrointestinal cancer immunotherapy. Front Immunol. 2025;16:1710880.
109. Huo R, Xu QG, You YQ, et al. Bifidobacterium boosts anti-PD-1 effectiveness through JAK pathway in hepatocellular carcinoma. NPJ Precis Oncol. 2025;9:251.
110. Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A. 2010;107:12204-9.
111. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell. 2005;122:107-18.
112. Mazmanian SK, Round JL, Kasper DL. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature. 2008;453:620-5.
113. Xiong H, Han X, Cai L, Zheng H. Natural polysaccharides exert anti-tumor effects as dendritic cell immune enhancers. Front Oncol. 2023;13:1274048.
114. Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell. 2015;161:264-76.
115. Sarrouilhe D, Clarhaut J, Defamie N, Mesnil M. Serotonin and cancer: what is the link? Curr Mol Med. 2015;15:62-77.
116. Seki E, De Minicis S, Österreicher CH, et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med. 2007;13:1324-32.
117. Soares JB, Pimentel-Nunes P, Roncon-Albuquerque R, Leite-Moreira A. The role of lipopolysaccharide/toll-like receptor 4 signaling in chronic liver diseases. Hepatol Int. 2010;4:659-72.
118. Vatanen T, Kostic AD, d’hennezel E, et al. ; DIABIMMUNE Study Group. Variation in microbiome LPS immunogenicity contributes to autoimmunity in humans. Cell. 2016;165:842-53.
119. Zhou Z, Xu MJ, Gao B. Hepatocytes: a key cell type for innate immunity. Cell Mol Immunol. 2015;13:301-15.
120. Dapito DH, Mencin A, Gwak G, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell. 2012;21:504-16.
121. Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20:375-88.
122. Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr. 2014;3:344-63.
123. Yan H, Zhong M, Yang J, et al. TLR5 activation in hepatocytes alleviates the functional suppression of intrahepatic CD8+ T cells. Immunology. 2020;161:325-44.
124. Shepard CR. TLR9 in MAFLD and NASH: at the intersection of inflammation and metabolism. Front Endocrinol. 2021;11:613639.
125. Li X, Zhang Q, Ding Y, et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol. 2016;17:806-15.
126. Harrington KJ, Brody J, Ingham M, et al. LBA15 - Preliminary results of the first-in-human (FIH) study of MK-1454, an agonist of stimulator of interferon genes (STING), as monotherapy or in combination with pembrolizumab (pembro) in patients with advanced solid tumors or lymphomas. Ann Oncol. 2018;29:ⅷ712.
127. Zitvogel L, Kroemer G. Cross-reactivity between microbial and tumor antigens. Curr Opin Immunol. 2022;75:102171.
128. Lee CH, Salio M, Napolitani G, Ogg G, Simmons A, Koohy H. Predicting cross-reactivity and antigen specificity of T cell receptors. Front Immunol. 2020;11:565096.
129. Boesch M, Baty F, Rothschild SI, et al. Tumour neoantigen mimicry by microbial species in cancer immunotherapy. Br J Cancer. 2021;125:313-23.
130. Zheng Z, Wieder T, Mauerer B, Schäfer L, Kesselring R, Braumüller H. T cells in colorectal cancer: unravelling the function of different T cell subsets in the tumor microenvironment. Int J Mol Sci. 2023;24:11673.
131. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079-84.
132. Leventhal DS, Sokolovska A, Li N, et al. Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity. Nat Commun. 2020;11:2739.
133. Zheng JH, Nguyen VH, Jiang SN, et al. Two-step enhanced cancer immunotherapy with engineeredSalmonella typhimurium secreting heterologous flagellin. Sci Transl Med. 2017;9:eaak9537.
134. Ghosh SS, Wang J, Yannie PJ, Ghosh S. Intestinal barrier function and metabolic/liver diseases. Liver Research. 2020;4:81-7.
135. Guerville M, Boudry G. Gastrointestinal and hepatic mechanisms limiting entry and dissemination of lipopolysaccharide into the systemic circulation. Am J Physiol Gastrointest Liver Physiol. 2016;311:G1-15.
136. Papadakos SP, Arvanitakis K, Stergiou IE, et al. The role of TLR4 in the immunotherapy of hepatocellular carcinoma: can we teach an old dog new tricks? Cancers. 2023;15:2795.
137. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat Rev Immunol. 2021;21:485-98.
138. Li Z, Luo J, Peng L, Wu B, Yu Z. Prognostic significance of systemic immune-inflammation index in hepatocellular carcinoma: a meta-analysis. Clin Transl Oncol. 2026;28:601-16.
139. Park SR, Kim G, Kim Y, et al. Fecal microbiota transplantation combined with anti-PD-1 inhibitor for unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor. J Clin Oncol. 2023;41:105.
140. Pomej K, Frick A, Scheiner B, et al. Fecal microbiota transplant combined with atezolizumab plus bevacizumab in patients with hepatocellular carcinoma who progressed on atezolizumab plus bevacizumab - interim analysis of the FAB-HCC phase II pilot study. Z Gastroenterol. 2024;62:e479-80.
141. 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.
142. Huang J, Zheng X, Kang W, et al. Metagenomic and metabolomic analyses reveal synergistic effects of fecal microbiota transplantation and anti-PD-1 therapy on treating colorectal cancer. Front Immunol. 2022;13:874922.
143. Lin A, Jiang A, Huang L, et al. From chaos to order: optimizing fecal microbiota transplantation for enhanced immune checkpoint inhibitors efficacy. Gut Microbes. 2025;17:2452277.
144. Li Z, Zhang Y, Hong W, et al. Gut microbiota modulate radiotherapy-associated antitumor immune responses against hepatocellular carcinoma via STING signaling. Gut Microbes. 2022;14:2119055.
145. Rauber C, Roberti MP, Vehreschild MJ, et al. Protocol: faecal microbiota transfer in liver cancer to overcome resistance to atezolizumab/bevacizumab - a multicentre, randomised, placebo-controlled, double-blind phase II trial (the FLORA trial). BMJ Open. 2025;15:e097802.
146. Abenavoli L, Montori M, Svegliati Baroni G, et al. Perspective on the role of gut microbiome in the treatment of hepatocellular carcinoma with immune checkpoint inhibitors. Medicina. 2023;59:1427.
147. Thilakarathna WPDW, Rupasinghe HPV, Ridgway ND. Mechanisms by which probiotic bacteria attenuate the risk of hepatocellular carcinoma. Int J Mol Sci. 2021;22:2606.
148. Gao G, Ma T, Zhang T, et al. Adjunctive probiotic lactobacillus rhamnosus Probio-M9 administration enhances the effect of Anti-PD-1 antitumor therapy via restoring antibiotic-disrupted gut microbiota. Front Immunol. 2021;12:772532.
149. 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.
150. Tanoue T, Morita S, Plichta DR, et al. A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 2019;565:600-5.
151. Suez J, Zmora N, Zilberman-Schapira G, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous FMT. Cell. 2018;174:1406-23.e16.
152. Liu X, Wang L, Jing N, Jiang G, Liu Z. Biostimulating gut microbiome with bilberry anthocyanin combo to enhance Anti-PD-L1 efficiency against murine colon cancer. Microorganisms. 2020;8:175.
153. Rong L, Ch’ng D, Jia P, Tsoi KKF, Wong SH, Sung JJY. Use of probiotics, prebiotics, and synbiotics in non‐alcoholic fatty liver disease: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2023;38:1682-94.
154. Nabavi S, Rafraf M, Somi MH, Homayouni-Rad A, Asghari-Jafarabadi M. Effects of probiotic yogurt consumption on metabolic factors in individuals with nonalcoholic fatty liver disease. J Dairy Sci. 2014;97:7386-93.
155. Ahn SB, Jun DW, Kang BK, Lim JH, Lim S, Chung MJ. Randomized, double-blind, placebo-controlled study of a multispecies probiotic mixture in nonalcoholic fatty liver disease. Sci Rep. 2019;9:5688.
156. Yang M, Chen W, Gupta D, et al. Nanoparticle/Engineered bacteria based triple-strategy delivery system for enhanced hepatocellular carcinoma cancer therapy. Int J Nanomedicine. 2024;19:3827-46.
157. Raman V, Van Dessel N, Hall CL, et al. Intracellular delivery of protein drugs with an autonomously lysing bacterial system reduces tumor growth and metastases. Nat Commun. 2021;12:6116.
158. Li Y, Wang X, Ye F, et al. Acid-responsive engineered bacteria with aberrant In-Situ anti-PD-1 expression for post-ablation immunotherapy of hepatocellular carcinoma. Biomed Pharmacother. 2025;186:118046.
159. Lin JH, Lin CH, Kuo YW, et al. Probiotic Lactobacillus fermentum TSF331, Lactobacillus reuteri TSR332, and Lactobacillus plantarum TSP05 improved liver function and uric acid management - a pilot study. PLoS One. 2024;19:e0307181.
160. Ye W, Chen Z, He Z, et al. Lactobacillus plantarum-derived postbiotics ameliorate acute alcohol-induced liver injury by protecting cells from oxidative damage, improving lipid metabolism, and regulating intestinal microbiota. Nutrients. 2023;15:845.
161. Guo Z, Yao Z, Chen X, et al. Mechanistic roles and intervention strategies involving gut microbiota, amino acid metabolism, and the tumor immune microenvironment in MAFLD-HCC progression. Clin Exp Med. 2025;26:31.
162. 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.
163. Hang S, Paik D, Yao L, et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature. 2019;576:143-8.
164. Ye G, Zhang H, Feng Q, Xiao J, Wang J, Liu J. Important role of bacterial metabolites in development and adjuvant therapy for hepatocellular carcinoma. Curr Oncol. 2025;32:673.
165. McBrearty N, Arzumanyan A, Bichenkov E, Merali S, Merali C, Feitelson M. Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice. Neoplasia. 2021;23:529-38.
166. Dean AE, Guzior DV, Quinn RA, Gaulke CA, Anakk S. Serum cholic acid and cecal Faecalibaculum increase in a male-specific manner in a murine hepatocellular carcinoma model. J Lipid Res. 2026;67:100954.
167. Pham YT, Wang R, Behari J, et al. Plant‐based diet index and risk of hepatocellular carcinoma: findings from a prospective cohort study. Int J Cancer. 2025;157:2463-75.
168. 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.
169. Li Y, Zhu T, Chen J, et al. Dual‐Targeted engineered bacterial outer membrane vesicles for hepatocellular carcinoma immunotherapy. Adv Funct Mater. 2024;34:2401355.
170. Eng L, Sutradhar R, Niu Y, et al. Impact of antibiotic exposure before immune checkpoint inhibitor treatment on overall survival in older adults with cancer: a population-based study. J Clin Oncol. 2023;41:3122-34.
