We identified through unbiased scRNA-seq and spatial transcriptomic approaches a novel tumor-cell intrinsic role of β-catenin-mediated IRF2 and POU2F1 repression driving an immune excluded TIME and inert type I/II interferon responses in β-catenin-mutated HCC with in vivo validation. The gene discussed is IRF2; the disease is hepatocellular carcinoma.