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

Area of Science:

• Hepatocellular Carcinoma Research
• Cancer Immunology
• RNA Therapeutics

Background:

• Hepatocellular carcinoma (HCC) with Wnt-active mutations (CTNNB1, AXIN1/2, APC) often shows limited response to immune checkpoint inhibitors (ICI) due to an excluded tumor microenvironment.
• Targeting CTNNB1 (encoding β-catenin) is a potential strategy for these HCC subsets.

Purpose of the Study:

• To evaluate the efficacy of a novel lipid nanoparticle-encapsulated siRNA targeting CTNNB1 (LNP-CTNNB1) in β-catenin-mutated HCC models.
• To investigate the impact of LNP-CTNNB1 on tumor microenvironment and immune responses.
• To assess the synergistic potential of LNP-CTNNB1 with ICI.

Main Methods:

• Utilized multiple immunocompetent HCC models with β-catenin mutations.
• Employed single-cell and spatial transcriptomics to analyze cellular and zonal changes.
• Assessed immune regulatory transcription factors (IRF2, POU2F1), interferon signaling, and innate/adaptive immune alterations.
• Evaluated LNP-CTNNB1 efficacy as monotherapy and in combination with ICI in advanced-stage disease.
• Analyzed patient data on lymphoid aggregates in relation to atezolizumab plus bevacizumab treatment response and survival.

Main Results:

• LNP-CTNNB1 demonstrated significant tumor responses in β-catenin-mutated HCC models.
• β-catenin suppression via LNP-CTNNB1 induced cellular and zonal reprogramming, activating IRF2 and POU2F1.
• Re-engagement of interferon signaling and alterations in innate and adaptive immunity were observed.
• LNP-CTNNB1 synergized with ICI, enhancing cytotoxic T cell recruitment in advanced disease.
• Decreased lymphoid aggregates in treated patients correlated with improved response and survival.

Conclusions:

• LNP-CTNNB1 is effective as a monotherapy and in combination with ICI for CTNNB1-mutated HCC.
• The therapy impacts tumor cell signaling and remodels immune surveillance, including T cell responses.
• Findings provide a strong rationale for clinical investigation of LNP-CTNNB1 in CTNNB1-mutated HCC.