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Nat. Commun., Jun 27 2025, 16 (1) | https://doi.org/10.1038/s41467-025-60894-z Hepatitis B virus promotes liver cancer by modulating the immune response to environmental carcinogens

Mei Huang^1,2,3,8, Dongyao Wang^1,2,4,8, Jiao Huang^1,2, An-Na Bae⁵, Yun Xia^1,2, Xutu Zhao^1,2, Mahsa Mortaja^1,2, Marjan Azin^1,2, Michael R. Collier⁶, Yevgeniy R. Semenov^6,7, Jong Ho Park^1,2,5 & Shadmehr Demehri^1,2

¹Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁴Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁵Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea.
⁶Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA.
⁸These authors contributed equally: Mei Huang, Dongyao Wang.

Corresponding authors
Correspondence to Jong Ho Park or Shadmehr Demehri.

Abstract

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.

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