Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8⁺ T cells, and also CD4⁺ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.

Background and Aims: Monocyte‐derived macrophages (MoMFs), a dominant population of hepatic macrophages under inflammation, play a crucial role in liver fibrosis progression. The spleen serves as an extra monocyte reservoir in inflammatory conditions; however, the precise mechanisms of involvement of the spleen in the pathogenesis of liver fibrosis remain unclear. Approach and Results: By splenectomy and splenocyte transfusion, it was observed that splenic CD11b⁺ cells accumulated intrahepatically as Ly6C^lo MoMFs to exacerbate CCl₄‐induced liver fibrosis. The splenocyte migration into the fibrotic liver was further directly visualized by spleen‐specific photoconversion with KikGR mice and confirmed by CD45.1⁺/CD45.2⁺ spleen transplantation. Spleen‐derived CD11b⁺ cells purified from fibrotic livers were then annotated by single‐cell RNA sequencing, and a subtype of CD11b⁺CD43^hiLy6C^lo splenic monocytes (sM‐1s) was identified, which was markedly expanded in both spleens and livers of mice with liver fibrosis. sM‐1s exhibited mature feature with high expressions of F4/80, produced much ROS, and manifested preferential migration into livers. Once recruited, sM‐1s underwent sequential transformation to sM‐2s (highly expressed Mif, Msr1, Clec4d, and Cstb) and then to spleen‐derived macrophages (sMφs) with macrophage features of higher expressions of CX₃CR1, F4/80, MHC class II, and CD64 in the fibrotic hepatic milieu. Furthermore, sM‐2s and sMφs were demonstrated capable of activating hepatic stellate cells and thus exacerbating liver fibrosis. Conclusions: CD11b⁺CD43^hiLy6C^lo splenic monocytes migrate into the liver and shift to macrophages, which account for the exacerbation of liver fibrosis. These findings reveal precise mechanisms of spleen–liver axis in hepatic pathogenesis and shed light on the potential of sM‐1 as candidate target for controlling liver diseases.

Hepatitis B virus (HBV) is a major risk factor for development of hepatocellular carcinoma (HCC), at least partially due to dysfunctional anti‐HBV adaptive immunity; however, the role of innate immune response to HBV in this process is not well understood. In this study, low‐dose polyinosinic:polycytidylic acid (poly [I:C]), a natural killer (NK) cell activator (3 μg/g body weight, twice/week for 8 weeks), induced HCC in HBV transgenic (HBs‐Tg) mice, with an incidence of 100% after 6 months, while HBs‐Tg mice without treatment only had HCC with an incidence of 16.7%. In HBs‐Tg mice, poly (I:C) induced liver inflammation with markedly increased infiltrating lymphocytes, along with the concurrently increased apoptosis and proliferation of hepatocytes, leading to the accelerated epithelial‐to‐mesenchymal transition (EMT) of hepatocytes shown by increased expression of the typical transcriptional factors (Slug, Twist, and mothers against decapentaplegic–interacting protein 1) and phenotypic proteins (vimentin and chemokine [C‐X‐C motif] receptor 4). The EMT and tumorigenesis in this model depended on the presence of NK cells because depletion of these cells significantly reduced the HCC rate to 28.6%. Further, intrahepatic NK cells highly expressed interferon‐gamma (IFN‐γ), anti‐IFN‐γ neutralizing monoclonal antibody might obviously alleviate the hepatitis, and hepatocyte‐specific IFN‐γ overexpression promoted HCC. Moreover, IFN‐γ deficiency in HBs‐Tg mice prevented HCC occurring, though hepatic NK cells existed and could be activated, suggesting the critical role of IFN‐γ in NK cell–mediated tumorigenesis. In an in vitro experiment, IFN‐γ up‐regulated epithelial cell adhesion molecule (EpCAM) expression through phosphorylated signal transducer and activator of transcription (p‐STAT1) pathway, which was followed by EMT, and p‐STAT1 inhibitor might absolutely abolish the expression of EpCAM and EMT in HBV surface antigen–positive hepatocytes. Conclusion: This work demonstrates that NK cell–derived IFN‐γ promotes HCC through the EpCAM–EMT axis in HBs‐Tg mice, revealing the importance of innate immunity in pathogenesis of HBV‐associated HCC.

Nonalcoholic steatohepatitis (NASH), a progressive form of nonalcoholic fatty liver disease (NAFLD), is accompanied by steatosis, hepatocyte injury and liver inflammation, which has been a health problem in the world as one of the major high risk factors of cirrhosis and hepatocellular carcinoma (HCC). Complex immune responses involving T cells, B cells, Kupffer cells, monocytes, neutrophils, DCs and other innate lymphocytes account for the pathogenesis of NASH; however, the underlying mechanisms have not been clearly elucidated in detail. In the liver, innate and innate-like lymphocytes account for more than two-thirds of total lymphocytes and play an important role in maintaining the immune homeostasis. Therefore, their roles in the progression of NASH deserves investigation. In this review, we summarized murine NASH models for immunological studies, including the diet-induced NASH, chemical-induced NASH and genetic-induced NASH. The role of innate and innate-like lymphocytes including NK cells, ILCs, NKT, γδT and MAIT cells in the progression of NASH were elucidated. Further, the metabolic regulation of the innate immune response was addressed in consideration to explain the molecular mechanisms. Based on the findings of the reviewed studies, strategies of immune intervention are proposed to control the progression of NASH.