Researchers from Japan identify “nucleocytosis,” a newly named cellular process with implications for immunity and drug development
Cells were long believed to safeguard nuclear contents, releasing them only during cell death. Extracellular DNA was thought to enter cells solely through endocytosis into endosomes, with self-DNA never reaching the cytosol directly. Challenging this view, researchers have discovered a previously unknown cellular phenomenon termed nucleocytosis, in which macrophages directly extract nuclear DNA from dying cells. This finding reshapes core cell biology concepts and may clarify immune responses, infections, cancer mechanisms, and future therapeutic development.
Over the years, cell biology has built a detailed picture of how cells compartmentalize their internal functions. Central to this organization is the nucleus, which houses the genetic material and is separated from the cytoplasm by a robust nuclear envelope. Traditionally, the nuclear membrane has been considered a strict barrier, maintaining nuclear integrity except during carefully controlled processes such as mitosis. As a result, the release of nuclear material has largely been associated with cellular damage or death.
However, recent work by a research team in Japan suggests that this view may be incomplete. While investigating immune-related cellular responses, the researchers observed unexpected behavior during interactions between immune cells and dying cells. Using experimental approaches combined with advanced imaging techniques, they tracked the movement of nuclear components under specific stimuli. To their surprise, nuclear DNA was selectively extracted from the nuclei of dying cells in a controlled and repeatable manner, without classical nuclear envelope breakdown or whole-cell phagocytosis.
Recognizing that this process differed fundamentally from any known cellular mechanism, the team identified it as a new phenomenon and named it nucleocytosis. The research was led by Professor Ken J. Ishii from the Department of Microbiology and Immunology at the Institute of Medical Science, The University of Tokyo, Japan, along with Dr. Hideo Negishi, project lecturer, Mr. Yusuke Wada, researcher from the same institute, and Dr. Yoshitaka Shirasaki, associate professor at Research Center for Advanced Science and Technology, The University of Tokyo, Japan. Their findings were published in Nature Communications on February 18, 2026.
Further experiments showed that nucleocytosis is not a random event but a regulated cellular function. This suggests that immune cells may intentionally access nuclear DNA from dying cells as part of regulated immune signaling processes. Such extracted nuclear DNA could act as molecular messengers, alerting the immune system or shaping inflammatory responses in ways that were previously unrecognized.
“The most striking aspect of our findings was realizing that cells possess an entirely new way to handle nuclear contents,” explains Dr. Negishi. “This discovery forces us to rethink how self-DNA activates immune response and how such activation can drive a variety of self-DNA-related diseases.”
The implications of nucleocytosis extend well beyond basic cell biology. Because immune recognition of nuclear material plays a key role in autoimmune diseases, infections, and cancer, understanding this pathway may help clarify disease mechanisms that have long remained elusive. In addition, nucleocytosis could represent a new target for therapeutic intervention, offering opportunities to regulate immune responses more precisely.
The motivation behind the study was also shaped by recent global health challenges. “During the spread of the novel coronavirus, many antiviral drugs were reported, but their mechanisms were largely unknown,” says Prof. Ishii. “I wanted to contribute to understanding how such drugs function at the cellular level and to support the development of new medications.”
In the short term, the discovery of nucleocytosis is expected to influence how cell biology is taught, potentially appearing in future textbooks as a newly defined cellular function. Over the longer term, insights gained from this research may directly inform drug development strategies. Within the next five to ten years, a deeper understanding of nucleocytosis could support the design of therapies for immune-related diseases, infections, and cancer, ultimately translating fundamental science into tangible benefits for society.
Fluorescence microscopy illustrates immune cell–mediated extraction of nuclear DNA from dying cells, highlighting a newly identified process called nucleocytosis.
Reference
Journal：Nature Communications
Title of original paper：
cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis
DOI：
10.1038/s41467-026-68839-w
Authors：
Hideo Negishi1,2,3,4,#, Yusuke Wada1,#, Yoshitaka Shirasaki5,#, Tomoya Hayashi1,2,4, Yuji Kubota6, Tomio Iwasaki7, Mina Kurosawa1, Tatsuma Ban8, Daisuke Muto9,26, Yusuke Suenaga9, Taichi Kojima1, Yuzuki Matsuda1, Sean Lord Irish1, Kosuke Dodo10,11, Toru Suzuki12, Mai Yamagishi13, Burcu Temizoz1,2,4, Atsushi Yoshimori14, Chisato Kanai15, Yoji Nagasaki16, Masaki Ohmuraya17, Tomohiko Tamura8,18, Atsushi Iwama4,19,20, Toshifumi Inada4,12, Etsushi Kuroda21, Kouji Kobiyama1,2,4,22, Noriko Toyama-Sorimachi2, Mutsuhiro Takekawa4,6,23, Cevayir Coban2,4,24, and Ken J. Ishii1,2,4,25
Affiliations：
1Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
2International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
3Laboratory of Immunology and Infection Control, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
4The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo, Japan
5Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
6Division of Cell Signaling and Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
7Research and Development Group, Hitachi, Ltd., Ibaraki, Japan
8Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
9Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba, Japan
10Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama, Japan
11Catalysis and Integrated Research Group, RIKEN Center for Sustainable Resource Science, Saitama, Japan
12Division of RNA and Gene Regulation, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
13Live Cell Diagnosis, Ltd., Saitama, Japan
14Institute for Theoretical Medicine, Inc., Kanagawa, Japan
15INTAGE Healthcare, Inc., Osaka, Japan
16Department of Pharmacy, NHO Kyushu Medical Center, Fukuoka, Japan
17Department of Genetics, School of Medicine, Hyogo Medical University, Hyogo, Japan
18Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan
19Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
20Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
21Department of Immunology, Hyogo Medical University School of Medicine, Hyogo, Japan
22Current address: Division of Rheumatology, Department of Medicine, University of California, San Diego, CA, USA
23Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
24Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
25Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
26School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Japan
#These authors contributed equally: Hideo Negishi, Yusuke Wada, and Yoshitaka Shirasaki
2International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
3Laboratory of Immunology and Infection Control, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
4The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center (UTOPIA), The University of Tokyo, Tokyo, Japan
5Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
6Division of Cell Signaling and Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
7Research and Development Group, Hitachi, Ltd., Ibaraki, Japan
8Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
9Laboratory of Evolutionary Oncology, Chiba Cancer Center Research Institute, Chiba, Japan
10Synthetic Organic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, Saitama, Japan
11Catalysis and Integrated Research Group, RIKEN Center for Sustainable Resource Science, Saitama, Japan
12Division of RNA and Gene Regulation, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
13Live Cell Diagnosis, Ltd., Saitama, Japan
14Institute for Theoretical Medicine, Inc., Kanagawa, Japan
15INTAGE Healthcare, Inc., Osaka, Japan
16Department of Pharmacy, NHO Kyushu Medical Center, Fukuoka, Japan
17Department of Genetics, School of Medicine, Hyogo Medical University, Hyogo, Japan
18Advanced Medical Research Center, Yokohama City University, Kanagawa, Japan
19Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
20Laboratory of Cellular and Molecular Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
21Department of Immunology, Hyogo Medical University School of Medicine, Hyogo, Japan
22Current address: Division of Rheumatology, Department of Medicine, University of California, San Diego, CA, USA
23Medical Proteomics Laboratory, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
24Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
25Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan
26School of Medical and Pharmaceutical Sciences, Chiba University, Chiba, Japan
#These authors contributed equally: Hideo Negishi, Yusuke Wada, and Yoshitaka Shirasaki
About the Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 130 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.About Professor Ken Ishii from the Institute of Medical Science, The University of Tokyo
Dr. Ken Ishii is a Professor at the Institute of Medical Science, the University of Tokyo, leading the Division of Vaccine Science in the Department of Microbiology and Immunology. He also serves as Director of the International Vaccine Design Center and Guest Professor at the Laboratory of Vaccine Science, IFReC, Osaka University. Prof. Ishii earned his M.D. and Ph.D. from Yokohama City University. His research focuses on advancing virus-based vectors for gene and cell therapies. His work advances molecular medicine through clinical translation.He has published 229 papers and received the Japanese Society of Immunology Award in December 2019.
Funding information
This study was supported by grants from JST CREST (JPMJCR18H1), JSPS KAKENHI (JP18K08406, JP21H02961), AMED (JP20ek0109319, JP223fa627001, JP223fa727001, and JP223fa727002, and JP21lm0203003), MUFJ Vaccine Development Project, the Joint Research Program of the Institute for Genetic Medicine, Hokkaido University, the International Joint Usage/Research Center (IMSUT, the University of Tokyo), MEXT Promotion of Distinctive Joint Research Center Program (JPMXP0724020288) at the Advanced Medical Research Center, Yokohama City University.Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp/