Hepatitis B virus promotes hepatocellular carcinoma (liver cancer) by modulating the immune response to environmental carcinogens

Hepatitis B virus (HBV) infection is a globally significant threaten to global health, with the potential to progress to hepatitis and hepatocellular carcinoma (HCC). Despite the availability of a vaccine, a population with non-responders, emphasizing the need for continued research into HBV-mediated immune responses. Interleukin-33 (IL-33) has emerged as a pivotal player in chronic inflammation and cancer, yet its role in specific viral contexts remains elusive. Here, we demonstrate the immune mechanisms underlying HBV infection and its contribution to HCC development. HBV with liver carcinogens induced IL-33 expression. Utilizing IL-33 and ST2 knockout mice, we demonstrate impaired HBV- mediated tumor progression, highlighting the critical involvement of IL-33 axis. Furthermore, we identify ST2 positive regulatory T cells (Treg) is a major effector cells with IL-33 in HBV-infected mice. ST2-deficient Tregs triggers immune cell infiltration, accompanied by reduced expression of immunosuppressive cytokines such as IL-10. Blocking this axis with STATIN, IL-33 inhibitor, shows promise therapeutic drug in chronic hepatitis and HCC in human subjects. In conclusion, our study reveals that IL-33/Treg axis as a critical mediator in hepatitis and its cancer development. Overall design: Whole liver RNA sequencing was performed on HBV-DEN and Sham-DEN mice at this time point. HBV-DEN group showed positive upregulation of hepatitis related genes compared to Sham-DEN mice by Gene Set Enrichment Analysis