In the current study, we investigate the relevance of RNAi-mediated β-catenin inhibition in patient-derived CTNNB1-mutated HCC organoids and multiple humanized mouse models of CTNNB1-mutated HCC at different treatment windows and elucidate the underlying mechanisms of response in both hepatic and immune compartments through both single-cell and spatial approaches. Here, CTNNB1 is linked to hepatocellular carcinoma.