Hepatitis B virus promotes hepatocellular carcinogenesis by activating IL-6-dependent tumor-macrophage crosstalk and M2-like macrophage polarization.

Hepatitis B virus X protein (HBx) is a prominent promoter of hepatitis B virus (HBV)-induced hepatocellular carcinoma (HCC) in the clinic, but the associated pro-tumorigenic mechanisms are still not well elucidated, especially its potential involvement in the tumor immunoevasion and immunotolerance. Surprisingly, we found that HBx expression status of HCC cells showed marked positive correlation with its interleukin 6 (IL-6) secretion, which drove M2 macrophage polarization via activating signal transducer and activator of transcription 3 (STAT3) signaling and fostered an immunosuppressive tumor microenvironment (TME). During this process, HBx partially translocated into mitochondria to cause mitochondrial DNA (mtDNA) leakage and activate absent in melanoma 2 (AIM2)-IL1β-nuclear factor kappa-B (NF-κB) signaling for boosting tumor-intrinsic IL-6 production. In line with these mechanistic insights, blocking IL-6 signaling in HBx-positive HCC tumors significantly revitalized the antitumor immune responses and retarded tumor growth, which also showed good synergy with programmed cell death protein 1 (PD-1) antibody therapy. Overall, this study revealed a non-canonical role of HBx in driving HCC progression while offering potential anti-HCC immunotherapeutic strategies.