Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancers Article Swipe
Brandon M. Lehrich
,
Evan R. Delgado
,
Tyler M. Yasaka
,
Silvia Liu
,
Catherine Cao
,
Y. Liu
,
Mohammad Taheri
,
Xiangnan Guan
,
Hartmut Koeppen
,
Sucha Singh
,
Vik Meadows
,
Jiajun Liu
,
Anya Singh‐Varma
,
Yekaterina Krutsenko
,
Minakshi Poddar
,
T. Kevin Hitchens
,
Lesley M. Foley
,
Bin-yong Liang
,
Alexander Rialdi
,
Parli Raghavan Ravi
,
Panari Patel
,
Madeline Riley
,
Aaron Bell
,
Reben Raeman
,
Tulin Dadali
,
Jason J. Luke
,
Ernesto Guccione
,
Mo R. Ebrahimkhani
,
Amaia Lujambio
,
Xin Chen
,
Martin A. Maier
,
Yulei Wang
,
Wendy Broom
,
Junyan Tao
,
Satdarshan P. Monga
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-025-60457-2
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1038/s41467-025-60457-2
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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1038/s41467-025-60457-2
- https://www.nature.com/articles/s41467-025-60457-2.pdf
- OA Status
- gold
- Cited By
- 9
- References
- 85
- Related Works
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- OpenAlex ID
- https://openalex.org/W4410843375
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4410843375Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1038/s41467-025-60457-2Digital Object Identifier
- Title
-
Precision targeting of β-catenin induces tumor reprogramming and immunity in hepatocellular cancersWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-05-29Full publication date if available
- Authors
-
Brandon M. Lehrich, Evan R. Delgado, Tyler M. Yasaka, Silvia Liu, Catherine Cao, Y. Liu, Mohammad Taheri, Xiangnan Guan, Hartmut Koeppen, Sucha Singh, Vik Meadows, Jiajun Liu, Anya Singh‐Varma, Yekaterina Krutsenko, Minakshi Poddar, T. Kevin Hitchens, Lesley M. Foley, Bin-yong Liang, Alexander Rialdi, Parli Raghavan Ravi, Panari Patel, Madeline Riley, Aaron Bell, Reben Raeman, Tulin Dadali, Jason J. Luke, Ernesto Guccione, Mo R. Ebrahimkhani, Amaia Lujambio, Xin Chen, Martin A. Maier, Yulei Wang, Wendy Broom, Junyan Tao, Satdarshan P. MongaList of authors in order
- Landing page
-
https://doi.org/10.1038/s41467-025-60457-2Publisher landing page
- PDF URL
-
https://www.nature.com/articles/s41467-025-60457-2.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.nature.com/articles/s41467-025-60457-2.pdfDirect OA link when available
- Concepts
-
Cancer research, HCCS, Reprogramming, Hepatocellular carcinoma, Wnt signaling pathway, Immune system, Medicine, Tumor microenvironment, Immune checkpoint, Gene signature, Immunology, Immunotherapy, Biology, Cell, Signal transduction, Gene, Gene expression, Cell biology, GeneticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
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9Total citation count in OpenAlex
- Citations by year (recent)
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2025: 9Per-year citation counts (last 5 years)
- References (count)
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85Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.First-line | 1 |
| abstract_inverted_index.IMbrave150 | 154 |
| abstract_inverted_index.LNP-CTNNB1 | 109, 120, 171 |
| abstract_inverted_index.Wnt-active | 21 |
| abstract_inverted_index.activation | 83 |
| abstract_inverted_index.aggregates | 134 |
| abstract_inverted_index.checkpoint | 3 |
| abstract_inverted_index.correlates | 160 |
| abstract_inverted_index.exhaustion | 128 |
| abstract_inverted_index.expression | 138 |
| abstract_inverted_index.interferon | 95 |
| abstract_inverted_index.preventing | 125 |
| abstract_inverted_index.re-engaged | 92 |
| abstract_inverted_index.regulatory | 86 |
| abstract_inverted_index.remodeling | 191 |
| abstract_inverted_index.signaling, | 96 |
| abstract_inverted_index.β-catenin | 106 |
| abstract_inverted_index.alterations | 98 |
| abstract_inverted_index.bevacizumab | 151 |
| abstract_inverted_index.combination | 178 |
| abstract_inverted_index.conclusion, | 170 |
| abstract_inverted_index.demonstrate | 35 |
| abstract_inverted_index.efficacious | 173 |
| abstract_inverted_index.monotherapy | 175 |
| abstract_inverted_index.significant | 51 |
| abstract_inverted_index.single-cell | 72 |
| abstract_inverted_index.suppression | 107 |
| abstract_inverted_index.atezolizumab | 149 |
| abstract_inverted_index.combinations | 6 |
| abstract_inverted_index.encapsulated | 64 |
| abstract_inverted_index.nanoparticle | 67 |
| abstract_inverted_index.β-catenin), | 28 |
| abstract_inverted_index.(LNP-CTNNB1). | 70 |
| abstract_inverted_index.-mutatational | 163 |
| abstract_inverted_index.heterogeneous | 36 |
| abstract_inverted_index.surveillance, | 194 |
| abstract_inverted_index.transcription | 87 |
| abstract_inverted_index.advanced-stage | 113, 122 |
| abstract_inverted_index.cell-intrinsic | 188 |
| abstract_inverted_index.hepatocellular | 12 |
| abstract_inverted_index.prognosticates | 144 |
| abstract_inverted_index.reprogramming, | 80 |
| abstract_inverted_index.immunocompetent | 57 |
| abstract_inverted_index.investigations. | 199 |
| abstract_inverted_index.transcriptomics | 75 |
| abstract_inverted_index.microenvironment. | 48 |
| abstract_inverted_index.β-catenin-mutated | 56 |
| cited_by_percentile_year.max | 99 |
| cited_by_percentile_year.min | 98 |
| countries_distinct_count | 2 |
| institutions_distinct_count | 35 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.7900000214576721 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.99168512 |
| citation_normalized_percentile.is_in_top_1_percent | True |
| citation_normalized_percentile.is_in_top_10_percent | True |