Here, we investigated the therapeutic potential of isoform-specific HIF-1α and HIF-2α antisense oligonucleotides (ASOs; provided by Ionis Pharmaceuticals), along with their effect on several TME-associated features, including inflammation and fibrosis, in a N,N-diethylnitrous amide (DEN)-induced HCC mouse model. This evidence concerns the gene HIF1A and hepatocellular carcinoma.