Uracil-DNA glycosylase deficiency is associated with repressed tumor cell-intrinsic inflammatory signaling and altered sensitivity to exogenous interferons

Sep 28, 2026

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2'-deoxyuridine (dU) is a prevalent DNA lesion in cancer, primarily repaired in genomic DNA by base excision repair initiated by Uracil-DNA glycosylase 2 (UNG2). Using Ung knockout B16 melanoma cells in an immunocompetent, syngeneic mouse model, the study finds UNG-deficient tumors show T cell–dependent delayed growth and increased responsiveness to anti-PD-L1 therapy. Immune profiling reveals reduced CD8+ infiltration but enhanced IFN-γ-competent effector CD4+ T cells. Mechanistically, UNG deficiency suppresses tumor cell-intrinsic type-I and type-II interferon and inflammatory gene signatures, alters cytokine/chemokine secretion, and changes sensitivity to exogenous interferons, increasing IFN-γ response while decreasing IFN-α/β sensitivity. Collectively, tumor-specific UNG loss remodels the inflammatory tumor microenvironment and supports a proof of concept for UNG inhibitors to modulate tumor inflammatory pathways.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Abstract

Introduction

NAR Cancer, 2025, 7, zcaf054 [https://doi.org/10.1093/narcan/zcaf054](https://doi.org/10.1093/narcan/zcaf054) DNA Damage Sensing and Repair Uracil-DNA glycosylase deficiency is associated with repressed tumor cell-intrinsic inflammatory signaling and altered sensitivity to exogenous interferons Frank P. Vendetti 1 ,* , Pinakin Pandya 1 , Carina R. Sclafani 1 , Sudipta Pathak 1 , Raquel Buj2 , Reyna E. Jones 1 , Daniel Ivanov3 , Katherine M. Aird2 , Robert W. Sobol 3 , Christopher J. Bakkenist 1,4,5 1 Department of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States 2 Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, United States 3 Department of Pathology and Laboratory Medicine, Warren Alpert Medical School & Legorreta Cancer Center, Brown University, Providence, RI, United States 4 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States 5 UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States ∗ To whom correspondence should be addressed. Email: [fpv3@pitt.edu](fpv3@pitt.edu) Abstract 2􀀃-deoxyuridine (dU) is a common DNA lesion resulting from cytosine deamination and from dUMP incorporation by DNA polymerases, both of which are prevalent in cancer. The primary mechanism that repairs dU lesions in genomic DNA is base excision repair initiated by UracilDNA Glycosylase 2 (UNG2) . We generated Ung knockout mouse B16 melanoma cells to investigate the consequences of UNG deficiency ina well-characterized, immunocompetent, syngeneic mouse cancer model. We show that UNG-deficient (􀀂UNG) B16 tumors exhibited T celldependent, delayed growth in vivo and were more responsive to anti-PD-L1 therapy. Immune profiling revealed reduced CD8+ T cell infiltration but augmented IFN-γ-competent effector CD4+ T cells in 􀀂UNG tumors. In vitro, 􀀂UNG tumor cells exhibited strongly suppressed cell-intrinsic type-I interferon, type-II interferon, and inflammatory signaling gene expression signatures as well as altered cytokine and chemokine secretion. In vivo, 􀀂UNG tumors exhibited a modified inflammatory cytokine and chemokine milieu. Furthermore, 􀀂UNG tumor cells had altered sensitivity to exogenous interferons in vitro, with increased sensitivity to IFN-γ but decreased sensitivity to IFN-α/β. Collectively, our data show that tumorcell-specific UNG deficiency results in an altered tumor microenvironment in vivo and provide proof of concept for the use of UNG inhibitors to modulate inflammatory pathways in tumors. Graphical abstract Introduction 2􀀃 -deoxyuridine (dU) is a common DNA lesion resulting from cytosine deamination and from dUMP incorporation by DNA polymerases, both of which are prevalent in cancer [1]. Many cancers harbor activating mutations in cytidine deaminases, driving widespread dU lesions, with cytidine deamination representing a major mutational signature in human cancers [2–4]. Additionally, many cancer patients receive antimetabo- Received: July 24, 2025. Revised: October 27, 2025. Accepted: November 23, 2025 © The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [reprints@oup.com](reprints@oup.com) for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [journals.permissions@oup.com](journals.permissions@oup.com). 2 Vendetti et al. lites including 5-fluoro

FAQs

What DNA lesion and repair pathway are central to this study?

The study focuses on 2'-deoxyuridine (dU) lesions and their repair via base excision repair initiated by Uracil-DNA glycosylase 2 (UNG2).

How does UNG deficiency affect tumor growth and response to anti-PD-L1 therapy?

Ung-deficient B16 tumors exhibit T cell–dependent delayed growth in vivo and are more responsive to anti-PD-L1 therapy.

How does UNG deficiency change interferon signaling and cytokine/chemokine patterns?

In vitro, UNG-deficient tumor cells show strongly suppressed type-I and type-II interferon and inflammatory gene expression, with altered cytokine and chemokine secretion. In vivo, they display a modified inflammatory cytokine and chemokine milieu and altered sensitivity to exogenous interferons, increasing IFN-γ sensitivity while decreasing IFN-α/β sensitivity.

Sep 28, 2026

Uploaded by SANS