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ResearchIn-Press PreviewGeneticsImmunologyOncology Open Access | 10.1172/jci.insight.184435

Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity

Eric S. Christenson,1 Brandon E. Smith,2 Thanh J. Nguyen,1 Alens Valentin,1 Soren Charmsaz,1 Nicole E Gross,1 Sarah M. Shin,1 Alexei Hernandez,1 Won Jin Ho,1 Srinivasan Yegnasubramanian,1 and James T. Stivers2

1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

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1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns, Johns Hopkins University School of Medicine, Baltimore, United States of America

2Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, United States of America

Find articles by Stivers, J. in: PubMed | Google Scholar

Published July 15, 2025 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.184435.
Copyright © 2025, Christenson et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 15, 2025 - Version history
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Abstract

Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in two mouse syngeneic models for colorectal cancer. Overexpressing the uracil DNA glycosylase inhibitor protein in mismatch repair (MMR)-deficient MC38 cells injected into C57/B6 mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared to FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared to FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into Balb/C mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG-depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune response in humans.

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