Targeting AATF reprograms the tumor microenvironment and suppresses hepatocellular carcinoma via MIR100HG–TGF-β signaling

Hepatocellular carcinoma (HCC), a leading cause of cancer death, has a dynamic and heterogeneous tumor microenvironment (TME) that drives progression and therapeutic resistance. We previously elucidated that apoptosis antagonizing transcription factor (AATF) drives angiogenesis in HCC. However, its role in TME remains unexplored. We employed an orthotopic xenograft mouse model, implanting human HCC cells into the liver, and achieved liver-specific silencing via tail vein injection of AAV8 carrying mouse-specific siAATF or siControl. Histological, biochemical, and molecular analyses, combined with whole-genome transcriptomics mapped to mouse and human genomes, were used to study TME and tumor compartments separately. Silencing of AATF in the TME significantly reduced tumor growth compared with controls. Furthermore, AATF loss disrupted key processes in TME, including inflammation, immune response, angiogenesis, and extracellular matrix remodeling. Mechanistically, TGF-β signaling was significantly suppressed in the TME, thereby affecting tumor cell cycle and metabolic activity, ultimately leading to tumor regression. The long noncoding RNA (lncRNA) analysis identified MIR100HG as a key downstream regulator of AATF in the TGF-β signaling pathway. These findings expand the oncogenic role of AATF to include regulation of the TME via the AATF–MIR100HG–TGF-β axis, highlighting its potential as a therapeutic target in HCC.