TIFA‐NF‐κB axis modulates inflammatory microenvironment to offset sorafenib cytotoxicity in hepatocellular carcinoma

Sorafenib is the promising first‐line drug to treat advanced hepatocellular carcinoma (HCC), with the acquired resistance within 6 months in most treated patients. The resistance to sorafenib treatment has been correlated to inflammation or viral hepatitis, but the underlying molecular mechanism remains elusive. We previously reported that the TRAF‐interacting protein TIFA sustains an inflammatory feedback loop of TNFα and NF‐κB to drive a survival pathway. Here we investigated how the inflammatory microenvironment is modulated by TIFA‐NF‐κB axis to confer a sorafenib‐resistant niche for HCC recurrence. The prognostic analysis showed that severe hepatitis was highly associated with poorer clinical responses to sorafenib treatment, suggesting that the sorafenib‐resistant HCC involves chronic inflammation. In support, inflammatory cytokines TNF‐α protected HCC lines form sorafenib cytotoxicity, while inhibition of TIFA‐NF‐κB axis reversed the effect. In addition, we showed that TIFA‐NF‐κB axis offset sorafenib cytotoxicity by supporting BCL‐2‐dependent survival signaling. To further explore the therapeutic relevance, we targeted TIFA‐NF‐κB axis using a liver‐tropic adeno‐associated virus to deliver shRNAs in an orthotopic xenograft HCC model, and result showed significant repression of tumor growth and prolonged animal survival in addition to sorafenib treatment. More intriguingly, such inhibition also abrogated the liver‐infiltration of tumor‐associated macrophages, a mechanistic event proven to be triggered by the TIFA‐NF‐κB‐regulated secretion of damage‐associated molecular pattern molecules S100A8/A9 in response to sorafenib, thereby recruiting precursor monocytes. As consequences of monocyte/macrophage infiltration, the TIFA‐NF‐κB axis in HCC cells compromised sorafenib cytotoxicity in alliance with pro‐tumor M2 macrophages, and harnessed their release of IL‐7 to enhance proliferation, sorafenib resistance, and directional migration of HCC cells. Our results collectively demonstrated that TIFA‐NF‐κB axis supports inflammatory responses to offset sorafenib cytotoxicity, and that its targeting provides therapeutically intervention concomitant with sorafenib treatment in HCC. Support or Funding Information This study was supported by Academia Sinica and the Taiwan Protein Project funded by Ministry of Science and Technology (MOST; Grant No. AS‐KPQ‐105‐TPP), and in part by grants MOST 104‐2314‐B‐182A‐060 and Chang Gung Memorial Hospital CMRPG3G0561.