We identified through unbiased bulk RNA-seq, scRNA-seq, and spatial transcriptomic approaches tumor-cell-intrinsic roles of β-catenin-mediated IRF2 and POU2F1 repression driving an immune-excluded TIME and inert type I/II IFN responses in β-catenin-mutated HCC with in vivo validation. This evidence concerns the gene IRF2 and neoplasm.