Tumor necrosis factor alpha (TNF-α) is a multi-functional cytokine that regulates a variety of signaling pathways implicated in
inflammation, immunity, cell death (apoptosis), cell survival (anti-apoptosis), and even tumorigenesis. TNF-α is predominantly produced
by macrophages (or Kupffer cells within the liver), but generated by lymphoid cells, astrocytes, endothelial cells, and smooth muscle
cells to some degree. In the liver, TNF-α not only serves as a key mediator of hepatocyte apoptosis resulting in the liver damage, but also
plays an important role in cellular proliferation leading to liver regeneration or even hepatocarcinogenesis. TNF-α may indirectly contribute
to carcinogenesis via various inflammatory conditions such as alcoholic and non-alcoholic fatty liver diseases and chronic viral hepatitis.
On the one hand, in inflammation, TNF-α induces apoptosis repeatedly and subsequently enhances the chance of formation of
anomalous cells during the process of regeneration and dysplasia. On the other hand, TNF-α exerts as an anti-angiogenic factor depending
on its concentration. It shows an anti-tumorous effect by increasing vascular permeability in the tumors. When it is perfused in combination
with chemotherapeutic drugs using isolated hepatic infusion, TNF-α may increase the responsiveness of hepatocellular carcinoma
(HCC) or metastatic cancers to anti-cancer agents as isolated limb perfusion methods in an unresectable soft tissue sarcoma or
melanoma. This article reviews the TNF-α signaling pathway in hepatocarcinogenesis and the new challenge of TNF-α as a new therapeutic
strategy in HCC.