Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers.

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in (encoding for β-catenin), , or , and demonstrate limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting (LNP-CTNNB1). Both single-cell and spatial transcriptomics revealed cellular and zonal reprogramming of -mutated tumors, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immune responses upon β-catenin suppression with LNP-CTNNB1. Moreover, LNP-CTNNB1 synergized with ICI in advanced-stage disease through orchestrating enhanced recruitment of cytotoxic T cell aggregates. Lastly, -mutated patients treated with atezolizumab plus bevacizumab combination had decreased presence of lymphoid aggregates, which were prognostic for response and survival. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in -mutated HCCs through impacting tumor cell intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.