Clearance of extracellular DNA prevents senescence-associated antitumor immunity
4 affiliations
- 1Department of Immunology, Shenzhen Majory Biotechnology Co., Ltd.
- 2Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences
- 3Department of Critical Care Medicine, Shenzhen Key Laboratory of Prevention and Treatment of Severe Infections, Shenzhen People’s Hospital, First Affiliated Hospital of Southern University of Science and Technology, Second Clinical Medicine College of Jinan University
- 4School of Life Science and Technology, China Pharmaceutical University
Abstract
Background: Tumor tissues are characterized by high tumor cell turnover, driven by oncogenic proliferation and counteracted by tumor-suppressive mechanisms such as apoptosis and senescence. Dying cancer cells go through apoptosis and release apoptotic particles containing fragmented DNA—which are chromatin- or nucleosome-bound—into the tumor microenvironment. Given the immunogenicity of extracellular DNA, its efficient clearance is crucial for cancer cells to evade immune defense. However, the consequences of failed clearance of these DNA fragments on cancer cells remain poorly defined.
Methods: To uncover the outcome of impaired extracellular DNA clearance in tumors, we disrupted this machinery in MMTV-PyMT spontaneous breast tumor mice by deleting both Dnase1l3 and Ighm (the immunoglobulin heavy chain), thereby eliminating the DNase and its compensatory autoantibodies, and monitored tumor progression and performed histopathological, molecular, and transcriptomic profiling on harvested tumors. To determine whether cGAS or TLR9 mediates this phenotype, we intercrossed these double-deficient mice with Sting1 -/- or Tlr9 -/- mice and assessed antitumor immunity when extracellular DNA clearance was abrogated.
Results: Combined deficiency of Dnase1l3 and anti-DNA autoantibody led to profound suppression of tumor growth in the MMTV-PyMT model. This antitumor effect was associated with senescence induction in cancer cells triggered by accumulation of uncleared extracellular chromatin DNA. Mechanistically, the senescence-associated antitumor immune response was driven by the cancer cell-intrinsic TLR9, but not cGAS.
Conclusions: Our findings establish that combined deficiency of Dnase1l3 and anti-DNA autoantibodies disrupts extracellular DNA clearance and elicits a TLR9-dependent senescence-associated antitumor immune response. This pathway may represent a tissue-level immunotherapeutic strategy for cancer.
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BibTeX
@article{wang2026clearance,
title = {{Clearance of extracellular DNA prevents senescence-associated antitumor immunity}},
author = {Yong Wang and Lijia Yuan and Mingzhu Zhu and Mengyao Li and Qingru Lin and Yuqian Zhang and Mengwei Li and Xueyan Liu and Shun Li},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1965273},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965273/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Clearance of extracellular DNA prevents senescence-associated antitumor immunity
AU - Yong Wang
AU - Lijia Yuan
AU - Mingzhu Zhu
AU - Mengyao Li
AU - Qingru Lin
AU - Yuqian Zhang
AU - Mengwei Li
AU - Xueyan Liu
AU - Shun Li
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1965273
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965273/full
AB - Background: Tumor tissues are characterized by high tumor cell turnover, driven by oncogenic proliferation and counteracted by tumor-suppressive mechanisms such as apoptosis and senescence. Dying cancer cells go through apoptosis and release apoptotic particles containing fragmented DNA—which are chromatin- or nucleosome-bound—into the tumor microenvironment. Given the immunogenicity of extracellular DNA, its efficient clearance is crucial for cancer cells to evade immune defense. However, the consequences of failed clearance of these DNA fragments on cancer cells remain poorly defined. Methods: To uncover the outcome of impaired extracellular DNA clearance in tumors, we disrupted this machinery in MMTV-PyMT spontaneous breast tumor mice by deleting both Dnase1l3 and Ighm (the immunoglobulin heavy chain), thereby eliminating the DNase and its compensatory autoantibodies, and monitored tumor progression and performed histopathological, molecular, and transcriptomic profiling on harvested tumors. To determine whether cGAS or TLR9 mediates this phenotype, we intercrossed these double-deficient mice with Sting1 -/- or Tlr9 -/- mice and assessed antitumor immunity when extracellular DNA clearance was abrogated. Results: Combined deficiency of Dnase1l3 and anti-DNA autoantibody led to profound suppression of tumor growth in the MMTV-PyMT model. This antitumor effect was associated with senescence induction in cancer cells triggered by accumulation of uncleared extracellular chromatin DNA. Mechanistically, the senescence-associated antitumor immune response was driven by the cancer cell-intrinsic TLR9, but not cGAS. Conclusions: Our findings establish that combined deficiency of Dnase1l3 and anti-DNA autoantibodies disrupts extracellular DNA clearance and elicits a TLR9-dependent senescence-associated antitumor immune response. This pathway may represent a tissue-level immunotherapeutic strategy for cancer.
SN - 1664-3224
ER -