1. Ferlay, J. et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer 136, E359–E386 (2015).

2. Llovet, J. M.et al Hepatocellular carcinoma. Nat. Rev. Dis. Prim. 2, 16018 (2016).

3. Bridgewater, J. et al. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J. Hepatol. 60, 1268–1289 (2014).

4. Bosman, F. T., Carneiro, F., Hruban, R. H. & Theise, N. D. WHO Classification of Tumours of The Digestive System. (World Health Organization, Geneva, 2010.

5. Liu, J. et al. Spontaneous seroclearance of hepatitis B seromarkers and subsequent risk of hepatocellular carcinoma. Gut 63, 1648–1657 (2014).

6. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).

7. Levrero, M. & Zucman-Rossi, J. Mechanisms of HBV-induced hepatocellular carcinoma. J. Hepatol. 64(Suppl), S84–S101 (2016).

8. Wong, V. W. et al. Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Lancet Gastroenterol. Hepatol. 1, 56–67 (2016).

9. Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 26, 331–343 (2014).

10. Loomba, R. & Sanyal, A. J. The global NAFLD epidemic. Nat. Rev. Gastroenterol. Hepatol. 10, 686–690 (2013).

11. Hernandez-Gea, V., Toffanin, S., Friedman, S. L. & Llovet, J. M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144, 512–527 (2013).

12. Fattovich, G., Stroffolini, T., Zagni, I. & Donato, F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 127, S35–S50 (2004).

13. Jörs, S. et al. Lineage fate of ductular reactions in liver injury and carcinogenesis. J. Clin. Invest. 125, 2445–2457 (2015).

14. Boege, Y. et al. A dual role of caspase-8 in triggering and sensing proliferation-associated DNA damage, a key determinant of liver cancer development. Cancer Cell. 32, 342–359 (2017).

15. Sia, D., Villanueva, A., Friedman, S. L. & Llovet, J. M. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152, 745–761 (2017).

16. Zucman-Rossi, J., Villanueva, A., Nault, J. C. & Llovet, J. M. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149, 1226–1239 (2015). e1224.

17. Villanueva, A., Hernandez-Gea, V. & Llovet, J. M. Medical therapies for hepatocellular carcinoma: a critical view of the evidence. Nat. Rev. Gastroenterol. Hepatol. 10, 34–42 (2013).

18. Naugler, W. E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

19. Subramaniam, A. et al. Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. Biochim. Biophys. Acta 1835, 46–60 (2013).

20. He, G. et al. Hepatocyte IKKβ/NF-κB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell. 17, 286–297 (2010).

21. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

22. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).

23. Haybaeck, J. et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 16, 295–308 (2009).

24. Sunami, Y. et al. Canonical NF-κB signaling in hepatocytes acts as a tumor-suppressor in hepatitis B virus surface antigen-driven hepatocellular carcinoma by controlling the unfolded protein response. Hepatology 63, 1592–1607 (2016).

25. Matter, M. S. et al. Oncogenic driver genes and the inflammatory microenvironment dictate liver tumor phenotype. Hepatology 63, 1888–1899 (2016).

26. Yuan, D. et al. Kupffer cell-derived TNF triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell. 31, 771–789 (2017).

27. Jenne, C. N. & Kubes, P. Immune surveillance by the liver. Nat. Immunol. 14, 996–1006 (2013).

28. Lumsden, A. B., Henderson, J. M. & Kutner, M. H. Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8, 232–236 (1988).

29. Notas, G., Kisseleva, T. & Brenner, D. NK and NKT cells in liver injury and fibrosis. Clin. Immunol. 130, 16–26 (2009).

30. Bricard, G. et al. Enrichment of human CD4+ V α 24 / V β 11 invariant NKT cells in intrahepatic malignant tumors. J. Immunol. 182, 5140–5151 (2009).

31. Protzer, U., Maini, M. K. & Knolle, P. A. Living in the liver: hepatic infections. Nat. Rev. Immunol. 12, 201–213 (2012).

32. Robinson, M. W., Harmon, C. & O’Farrelly, C. Liver immunology and its role in inflammation and homeostasis. Cell. Mol. Immunol. 13, 267–276 (2016).

33. Heymann, F. et al. Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Hepatology 62, 279–291 (2015).

34. Helmy, K. Y. et al. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell 124, 915–927 (2006).

35. Tacke, F. Targeting hepatic macrophages to treat liver diseases. J. Hepatol. 66, 1300–1312 (2017).

36. Knolle, P. A. et al. Endotoxin down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells. J. Immunol. 162, 1401–1407 (1999).

37. Huang, L. R. et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8+ T cells and successful immunotherapy against chronic viral liver infection. Nat. Immunol. 14, 574–583 (2013).

38. Medina-Echeverz, J., Eggert, T., Han, M. & Greten, T. F. Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunol. Immunother. 64, 931–940 (2015).

39. Kelly, A. et al. CD141+ myeloid dendritic cells are enriched in healthy human liver. J. Hepatol. 60, 135–142 (2014).

40. Pallett, L. J. et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat. Med. 21, 591–600 (2015).

41. Knolle, P. A. et al. Interleukin-10 expression is autoregulated at the transcriptional level in human and murine Kupffer cells. Hepatology 27, 93–99 (1998).

42. Wu, J. et al. Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology 129, 363–374 (2010).

43. Diehl, L. et al. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47, 296–305 (2008).

44. Limmer, A. et al. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat. Med. 6, 1348–1354 (2000).

45. Huang, L., Soldevila, G., Leeker, M., Flavell, R. & Crispe, I. N. The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity 1, 741–749 (1994).

46. Ringelhan, M., McKeating, J. A. & Protzer, U. Viral hepatitis and liver cancer. Phil. Trans. R. Soc. Lond. B https://doi.org/10.1098/rstb.2016.0274 (2017).

47. Knolle, P. A. & Thimme, R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146, 1193–1207 (2014).

48. Wieland, D., Hofmann, M. & Thimme, R. Overcoming CD8+ T-cell exhaustion in viral hepatitis: lessons from the mouse model and clinical perspectives. Dig. Dis. 35, 334–338 (2017).

49. Lopes, A. R. et al. Bim-mediated deletion of antigen-specific CD8 T cells in patients unable to control HBV infection. J. Clin. Invest. 118, 1835–1845 (2008).

50. Das, A. et al. Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J. Exp. Med. 205, 2111–2124 (2008).

51. Hedegaard, D. L. et al. High resolution sequencing of hepatitis C virus reveals limited intra-hepatic compartmentalization in end-stage liver disease. J. Hepatol. 66, 28–38 (2017).

52. Li, X. D., Sun, L., Seth, R. B., Pineda, G. & Chen, Z. J. Hepatitis C virus protease NS3/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity. Proc. Natl Acad. Sci. USA 102, 17717–17722 (2005).

53. Meylan, E. et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature 437, 1167–1172 (2005).

54. Ahlén, G. et al. Cleavage of the IPS-1/Cardif/MAVS/VISA does not inhibit T cell-mediated elimination of hepatitis C virus non-structural 3/4A-expressing hepatocytes. Gut 58, 560–569 (2009).

55. Wieland, D. et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat. Commun. 8, 15050 (2017).

56. Chattergoon, M. A. et al. HIV and HCV activate the inflammasome in monocytes and macrophages via endosomal Toll-like receptors without induction of type 1 interferon. PLoS. Pathog. 10, e1004082 (2014).

57. Szabo, G. & Petrasek, J. Inflammasome activation and function in liver disease. Nat. Rev. Gastroenterol. Hepatol. 12, 387–400 (2015).

58. European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J. Hepatol. 57, 399–420 (2012).

59. Iracheta-Vellve, A. et al. Inhibition of sterile danger signals, uric acid and ATP, prevents inflammasome activation and protects from alcoholic steatohepatitis in mice. J. Hepatol. 63, 1147–1155 (2015).

60. Ge, X. et al. High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J. Biol. Chem. 289, 22672–22691 (2014).

61. Petrasek, J., Csak, T., Ganz, M. & Szabo, G. Differences in innate immune signaling between alcoholic and non-alcoholic steatohepatitis. J. Gastroenterol. Hepatol. 28 (Suppl 1), 93–98 (2013).

62. Wolf, M. J. et al. Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Cancer Cell. 26, 549–564 (2014).

63. Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).

64. Hassin, D., Garber, O. G., Meiraz, A., Schiffenbauer, Y. S. & Berke, G. Cytotoxic T lymphocyte perforin and Fas ligand working in concert even when Fas ligand lytic action is still not detectable. Immunology 133, 190–196 (2011).

65. Guidotti, L. G. et al. Immunosurveillance of the liver by intravascular effector CD8+ T cells. Cell 161, 486–500 (2015).

66. Lucifora, J. et al. Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA. Science 343, 1221–1228 (2014).

67. Chiang, E. Y. et al. Targeted depletion of lymphotoxin-α-expressing T H 1 and T H 17 cells inhibits autoimmune disease. Nat. Med. 15, 766–773 (2009).

68. Finkin, S. et al. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16, 1235–1244 (2015).

69. Endig, J. et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell. 30, 308–323 (2016).

70. Flecken, T. et al. Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).

71. Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).

72. Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).

73. Fu, J. et al. Impairment of CD4+ cytotoxic T cells predicts poor survival and high recurrence rates in patients with hepatocellular carcinoma. Hepatology 58, 139–149 (2013).

74. Sautès-Fridman, C.et al Tertiary Lymphoid structures in cancers: prognostic value, regulation, and manipulation for therapeutic intervention. Front. Immunol. 7, 407 (2016)..

75. Coppola, D. et al. Unique ectopic lymph node-like structures present in human primary colorectal carcinoma are identified by immune gene array profiling. Am. J. Pathol. 179, 37–45 (2011).

76. Messina, J. L. et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci. Rep. 2, 765 (2012).

77. Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).

78. Dimeloe, S., Burgener, A. V., Grählert, J. & Hess, C. T-cell metabolism governing activation, proliferation and differentiation; a modular view. Immunology 150, 35–44 (2017).

79. Gomes, A. L. et al. Metabolic inflammation-associated IL-17A causes non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Cell. 30, 161–175 (2016).

80. Jia, Y. et al. Impaired function of CD4+ T follicular helper (Tfh) cells associated with hepatocellular carcinoma progression. PLoS. One 10, e0117458 (2015).

81. Schneider, C. et al. Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer. Gut 61, 1733–1743 (2012).

82. Xue, H. et al. Overrepresentation of IL-10-expressing b cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. PLoS. One 11, e0154815 (2016).

83. Syn, W. K. et al. NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Gut 61, 1323–1329 (2012).

84. Syn, W. K. et al. Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Hepatology 51, 1998–2007 (2010).

85. Anson, M. et al. Oncogenic β-catenin triggers an inflammatory response that determines the aggressiveness of hepatocellular carcinoma in mice. J. Clin. Invest. 122, 586–599 (2012).

86. Gur, C. et al. NKp46-mediated killing of human and mouse hepatic stellate cells attenuates liver fibrosis. Gut 61, 885–893 (2012).

87. Sui, Q. et al. NK cells are the crucial antitumor mediators when STAT3-mediated immunosuppression is blocked in hepatocellular carcinoma. J. Immunol. 193, 2016–2023 (2014).

88. Sun, C. et al. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. OncoImmunology 6, e1264562 (2016).

89. Zhang, Q. F. et al. Liver-infiltrating CD11b–CD27– NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell. Mol. Immunol. 14, 819–829 (2017).

90. Lee, J. H. et al. Adjuvant immunotherapy with autologous cytokine-induced killer cells for hepatocellular carcinoma. Gastroenterology 148, 1383–1391 (2015).

91. Kahraman, A. et al. Major histocompatibility complex class I-related chains A and B (MIC A/B): a novel role in nonalcoholic steatohepatitis. Hepatology 51, 92–102 (2010).

92. Tosello-Trampont, A. C. et al. NKp46+ natural killer cells attenuate metabolism-induced hepatic fibrosis by regulating macrophage activation in mice. Hepatology 63, 799–812 (2016).

93. Li, X. et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut 66, 157–167 (2017).

94. Ehling, J. et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 63, 1960–1971 (2014).

95. Garcia-Martinez, I. et al. Hepatocyte mitochondrial DNA drives nonalcoholic steatohepatitis by activation of TLR9. J. Clin. Invest 126, 859–864 (2016).

96. Koh, M. Y. et al. A new HIF-1α/RANTES-driven pathway to hepatocellular carcinoma mediated by germline haploinsufficiency of SART1/HAF in mice. Hepatology 63, 1576–1591 (2016).

97. Greten, F. R. et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 130, 918–931 (2007).

98. Robert, O. et al. Decreased expression of the glucocorticoid receptor-GILZ pathway in Kupffer cells promotes liver inflammation in obese mice. J. Hepatol. 64, 916–924 (2016).

99. Fan, Z. et al. The histone methyltransferase Suv39h2 contributes to nonalcoholic steatohepatitis in mice. Hepatology 65, 1904–1919 (2017).

100. Svendsen, P. et al. Antibody-directed glucocorticoid targeting to CD163 in M2-type macrophages attenuates fructose-induced liver inflammatory changes. Mol. Ther. Methods Clin. Dev. 4, 50–61 (2016).

101. Reid, D. T. et al. Kupffer cells undergo fundamental changes during the development of experimental NASH and are critical in initiating liver damage and inflammation. PLoS. One 11, e0159524 (2016).

102. Baeck, C. et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut 61, 416–426 (2012).

103. Kong, L.et al Deletion of interleukin-6 in monocytes/macrophages suppresses the initiation of hepatocellular carcinoma in mice. J. Exp. Clin. Cancer Res. 35, 131 (2016)..

104. Sun, K. et al. Autophagy-deficient Kupffer cells promote tumorigenesis by enhancing mtROS-NF-κB-IL1α/β-dependent inflammation and fibrosis during the preneoplastic stage of hepatocarcinogenesis. Cancer Lett. 388, 198–207 (2017).

105. Kessoku, T. et al. Resveratrol ameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci. Rep. 6, 22251 (2016).

106. Lacotte, S. et al. Impact of myeloid-derived suppressor cell on Kupffer cells from mouse livers with hepatocellular carcinoma. OncoImmunology 5, e1234565 (2016).

107. Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell. 30, 533–547 (2016).

108. Connolly, M. K. et al. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF-alpha. J. Clin. Invest. 119, 3213–3225 (2009).

109. Henning, J. R. et al. Dendritic cells limit fibroinflammatory injury in nonalcoholic steatohepatitis in mice. Hepatology 58, 589–602 (2013).

110. Sutti, S. et al. CX3CR1-expressing inflammatory dendritic cells contribute to the progression of steatohepatitis. Clin. Sci. 129, 797–808 (2015).

111. Heier, E. C. et al. Murine CD103+ dendritic cells protect against steatosis progression towards steatohepatitis. J. Hepatol. 66, 1241–1250 (2017).

112. Rai, V. et al. Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma. Mol. Cell. Biochem. 437, 13–36 (2017).

113. Cheng, J. T. et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis 5, e198 (2016).

114. Pedroza-Gonzalez, A. et al. Tumor-infiltrating plasmacytoid dendritic cells promote immunosuppression by Tr1 cells in human liver tumors. OncoImmunology 4, e1008355 (2015).

115. Ouyang, F. Z. et al. Dendritic cell-elicited B-cell activation fosters immune privilege via IL-10 signals in hepatocellular carcinoma. Nat. Commun. 7, 13453 (2016).

116. Wiedemann, G. M. et al. Cancer cell-derived IL-1α induces CCL22 and the recruitment of regulatory T cells. OncoImmunology 5, e1175794 (2016).

117. Li, X. et al. Neutrophil count is associated with myeloid derived suppressor cell level and presents prognostic value of for hepatocellular carcinoma patients. Oncotarget 8, 24380–24388 (2017).

118. Personeni, N. et al. Prognostic value of the neutrophil-to-lymphocyte ratio in the ARQ 197-215 second-line study for advanced hepatocellular carcinoma. Oncotarget 8, 14408–14415 (2017).

119. Xu, R., Huang, H., Zhang, Z. & Wang, F. S. The role of neutrophils in the development of liver diseases. Cell. Mol. Immunol. 11, 224–231 (2014).

120. Zang, S. et al. Increased ratio of neutrophil elastase to α1-antitrypsin is closely associated with liver inflammation in patients with nonalcoholic steatohepatitis. Clin. Exp. Pharmacol. Physiol. 43, 13–21 (2016).

121. Ibusuki, R. et al. Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet. Liver Int. 33, 1549–1556 (2013).

122. Zhou, S. L. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150, 1646–1658 (2016).

123. Meyer, T. et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol. Hepatol. 2, 565–575 (2017).

124. Llovet, J. M. & Hernandez-Gea, V. Hepatocellular carcinoma: reasons for phase III failure and novel perspectives on trial design. Clin. Cancer Res. 20, 2072–2079 (2014).

125. Totoki, Y. et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat. Genet. 46, 1267–1273 (2014).

126. Schulze, K. et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 47, 505–511 (2015).

127. Sia, D. et al. Identification of an immune-specific class of hepatocellular carcinoma, based on molecular features. Gastroenterology 153, 812–826 (2017).

128. Schlageter, M. et al. Clinicopathological features and metastatic pattern of hepatocellular carcinoma: an autopsy study of 398 patients. Pathobiology 83, 301–307 (2016).

129. Nault, J. C. & Zucman-Rossi, J. TERT promoter mutations in primary liver tumors. Clin. Res. Hepatol. Gastroenterol. 40, 9–14 (2016).

130. Spear, T. T. et al. TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors. Cancer Immunol. Immunother. 65, 293–304 (2016).

131. Hiroishi, K. et al. Strong CD8+ T-cell responses against tumor-associated antigens prolong the recurrence-free interval after tumor treatment in patients with hepatocellular carcinoma. J. Gastroenterol. 45, 451–458 (2010).

132. Sun, Z. et al. Status of and prospects for cancer vaccines against hepatocellular carcinoma in clinical trials. Biosci. Trends 10, 85–91 (2016).

133. Mizukoshi, E. et al. Enhancement of tumor-associated antigen-specific T cell responses by radiofrequency ablation of hepatocellular carcinoma. Hepatology 57, 1448–1457 (2013).

134. Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

135. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

136. Brunner, S. M. et al. Tumor-infiltrating, interleukin-33-producing effector-memory CD8+ T cells in resected hepatocellular carcinoma prolong patient survival. Hepatology 61, 1957–1967 (2015).

137. Chen, J. et al. Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint. Oncotarget 7, 41274–41284 (2016).

138. Harding, J. J., El Dika, I. & Abou-Alfa, G. K. Immunotherapy in hepatocellular carcinoma: primed to make a difference? Cancer 122, 367–377 (2016).

139. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356 (2017).

140. Xie, Q. K. et al. Programmed death ligand 1 as an indicator of pre-existing adaptive immune responses in human hepatocellular carcinoma. OncoImmunology 5, e1181252 (2016).

141. Sideras, K. et al. PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma. OncoImmunology 6, e1273309 (2017).

142. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 27, 450–461 (2015).

143. Okazaki, T., Chikuma, S., Iwai, Y., Fagarasan, S. & Honjo, T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat. Immunol. 14, 1212–1218 (2013).

144. El-Khoueiry, A. B. 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 389, 2492–2502 (2017).

145. Sangro, B. et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J. Hepatol. 59, 81–88 (2013).

146. Nault, J. C. The end of almost 10 years of negative RCTs in advanced hepatocellular carcinoma. Lancet 389, 4–6 (2017).

147. Duffy, A. G. et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J. Hepatol. 66, 545–551 (2017).

148. Shen, Y. et al. TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization. Cell. Physiol. Biochem. 35, 1623–1632 (2015).

149. Wang, Y. et al. Hepatocellular carcinoma cells induce regulatory T cells and lead to poor prognosis via production of transforming growth factor-β1. Cell. Physiol. Biochem. 38, 306–318 (2016).