CRISPR-Induced NUT Suppression Promotes Differentiation and Enhances Trop2-Targeted Immunocytokine Response in NUT Carcinoma Article Swipe
Juyoung Choi
,
Daesik Kim
,
Joo Youn Oh
,
Hee Geon Park
,
Hwa Lin Yi
,
Yurimi Lee
,
Hoyeon Jeong
,
Jiyoung Song
,
Minjung Sung
,
Eun Sol Chang
,
Kyungsoo Jung
,
Saehyung Lee
,
Young Kee Shin
,
Se‐Hoon Lee
,
Christopher A. French
,
Mi-Sook Lee
,
Yoon–La Choi
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.28.685224
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.28.685224
NUT carcinoma (NC) is an aggressive malignancy driven by NUTM1 gene rearrangements with limited therapeutic options. Here, we show that direct suppression of NUTM1 using CRISPR/Cas9 induces squamous-like differentiation and upregulates TROP2 expression in NC cells. Building on this finding, we developed a TROP2–interferon beta (IFN-β) mutein immunocytokine that selectively targets TROP2-expressing tumors. Combined NUTM1 suppression and TROP2-targeted immunotherapy synergistically enhanced cytotoxic and immune-mediated responses in vitro . Transcriptomic and spatial analyses of NC patient tumors revealed that differentiation status correlates with TROP2 expression, upregulated immune pathways, and favorable clinical outcomes. Our results suggest that overcoming differentiation blockade not only alters tumor phenotype but also creates a more immune-permissive microenvironment. These findings highlight the therapeutic potential of sequential tumor reprogramming followed by targeted immunotherapy in treating NC and propose a broader strategy for overcoming differentiation blockade in fusion-driven cancers.
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- article
- Landing Page
- https://doi.org/10.1101/2025.10.28.685224
- OA Status
- green
- References
- 52
- OpenAlex ID
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https://openalex.org/W4415746873Canonical identifier for this work in OpenAlex
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https://doi.org/10.1101/2025.10.28.685224Digital Object Identifier
- Title
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CRISPR-Induced NUT Suppression Promotes Differentiation and Enhances Trop2-Targeted Immunocytokine Response in NUT CarcinomaWork title
- Type
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articleOpenAlex work type
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2025Year of publication
- Publication date
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2025-10-31Full publication date if available
- Authors
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Juyoung Choi, Daesik Kim, Joo Youn Oh, Hee Geon Park, Hwa Lin Yi, Yurimi Lee, Hoyeon Jeong, Jiyoung Song, Minjung Sung, Eun Sol Chang, Kyungsoo Jung, Saehyung Lee, Young Kee Shin, Se‐Hoon Lee, Christopher A. French, Mi-Sook Lee, Yoon–La ChoiList of authors in order
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https://doi.org/10.1101/2025.10.28.685224Publisher landing page
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greenOpen access status per OpenAlex
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https://doi.org/10.1101/2025.10.28.685224Direct OA link when available
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0Total citation count in OpenAlex
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52Number of works referenced by this work
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