Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens

Hepatitis B virus (HBV) infection is associated with hepatitis and hepatocellular carcinoma (HCC). Considering that most HBV-infected individuals remain asymptomatic, the mechanism linking HBV to hepatitis and HCC remains uncertain. Herein, we demonstrate that HBV alone does not cause liver inflammation or cancer. Instead, HBV alters the chronic inflammation induced by chemical carcinogens to promote liver carcinogenesis. Long-term HBV genome expression in mouse liver increases liver inflammation and cancer propensity caused by a carcinogen, diethylnitrosamine (DEN). HBV plus DEN-activated interleukin-33 (IL-33)/regulatory T cell axis is required for liver carcinogenesis. Pitavastatin, an IL-33 inhibitor, suppresses HBV plus DEN-induced liver cancer. IL-33 is markedly elevated in HBV⁺ hepatitis patients, and pitavastatin use significantly correlates with reduced risk of hepatitis and its associated HCC in patients. Collectively, our findings reveal that environmental carcinogens are the link between HBV and HCC risk, creating a window of opportunity for cancer prevention in HBV carriers.