AATF silencing suppresses tumor progression by reprogramming the microenvironment in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. It is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) that promotes disease progression and therapeutic resistance. The TME plays a crucial role in the progression of HCC by regulating immune response, extracellular matrix remodeling, and angiogenesis. We previously elucidated that apoptosis antagonizing transcription factor (AATF) drives angiogenesis in HCC. However, its role in TME remains unexplored. Here, we studied the effect of AATF silencing in TME on HCC progression using an orthotopic xenograft model. Mice were injected with liver-specific AAV8 carrying siAATF or siControl and monitored for tumor growth. Whole transcriptomics and molecular analyses were carried out. AATF silencing reduced tumor growth and invasion. Species-specific transcriptomic analysis showed that the TME signatures like inflammation, immune response, angiogenesis, and ECM remodeling were altered in siAATF mice compared to the siControl. Mechanistically, TGF-β signaling was markedly suppressed in the TME affecting the cell cycle and metabolic activity of tumor cells, leading to tumor regression. These findings highlight AATF as a critical regulator of the TME, offering novel insights into potential therapeutic targets for HCC.