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

Brandon M. Lehrich, Evan R. Delgado, Tyler M. Yasaka, Silvia Liu, Catherine Cao, Yuqing Liu, Mohammad N. Taheri, Xiangnan Guan, Hartmut Koeppen, Sucha Singh, Vik Meadows, Jia-Jun Liu, Anya Singh-Varma, Yekaterina Krutsenko, Minakshi Poddar, T. Kevin Hitchens, Lesley M. Foley, Binyong Liang, Alex Rialdi, Ravi P. Rai, Panari Patel, Madeline Riley, Aaron Bell, Reben Raeman, Tulin Dadali, Jason J. Luke, Ernesto Guccione, Mo R. Ebrahimkhani, Amaia Lujambio, Xin Chen, Martin Maier, Yulei Wang, Wendy Broom, Junyan Tao () and Satdarshan P. Monga ()
Additional contact information
Brandon M. Lehrich: University of Pittsburgh School of Medicine
Evan R. Delgado: University of Pittsburgh and University of Pittsburgh Medical Center
Tyler M. Yasaka: University of Pittsburgh School of Medicine
Silvia Liu: University of Pittsburgh School of Medicine
Catherine Cao: University of Pittsburgh School of Medicine
Yuqing Liu: University of Pittsburgh School of Medicine
Mohammad N. Taheri: University of Pittsburgh and University of Pittsburgh Medical Center
Xiangnan Guan: Genentech Inc.
Hartmut Koeppen: Genentech Inc.
Sucha Singh: University of Pittsburgh School of Medicine
Vik Meadows: University of Pittsburgh School of Medicine
Jia-Jun Liu: University of Pittsburgh School of Medicine
Anya Singh-Varma: University of Pittsburgh School of Medicine
Yekaterina Krutsenko: University of Pittsburgh School of Medicine
Minakshi Poddar: University of Pittsburgh School of Medicine
T. Kevin Hitchens: University of Pittsburgh School of Medicine
Lesley M. Foley: University of Pittsburgh School of Medicine
Binyong Liang: Huazhong University of Science and Technology
Alex Rialdi: Icahn School of Medicine at Mount Sinai
Ravi P. Rai: University of Pittsburgh School of Medicine
Panari Patel: University of Pittsburgh School of Medicine
Madeline Riley: University of Pittsburgh School of Medicine
Aaron Bell: University of Pittsburgh School of Medicine
Reben Raeman: University of Pittsburgh School of Medicine
Tulin Dadali: Alnylam Pharmaceuticals
Jason J. Luke: UPMC Hillman Cancer Center and University of Pittsburgh
Ernesto Guccione: Icahn School of Medicine at Mount Sinai
Mo R. Ebrahimkhani: University of Pittsburgh and University of Pittsburgh Medical Center
Amaia Lujambio: Icahn School of Medicine at Mount Sinai
Xin Chen: University of Hawaii Cancer Center
Martin Maier: Alnylam Pharmaceuticals
Yulei Wang: Genentech Inc.
Wendy Broom: Alnylam Pharmaceuticals
Junyan Tao: University of Pittsburgh School of Medicine
Satdarshan P. Monga: University of Pittsburgh School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-26

Abstract: Abstract 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 CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and 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 CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, 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 immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations.

Date: 2025
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DOI: 10.1038/s41467-025-60457-2

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