2. Academic Validation
  3. Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity

Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity

  • Cancer Cell. 2026 May 11;44(5):965-982.e12. doi: 10.1016/j.ccell.2026.03.023.
Mengying Hu 1,  Di-Ao Liu 2,  Inbal Wortzel 2,  Paul Collier 3,  Theodore M Nelson 3,  Jonathan Foox 3,  Guojie Zhong 4,  Gabriel Tobias 2,  Tetsuhiko Asao 5,  Linda Bojmar 6,  Candia M Kenific 2,  Gang Wang 2,  Simone Caielli 7,  Zurong Wan 7,  Sarah Qureshy 2,  Max Reed 2,  Richard Piszczatowski 2,  Purnima Ravisankar 7,  Julia A Brown 7,  Sihan Xiong 2,  Huajuan Wang 2,  Pernille Lauritzen 2,  Yael Aylon 8,  Henrik Molina 9,  William R Jarnagin 10,  Moshe Oren 8,  Ben Z Stanger 11,  Jack Bui 12,  Gabriele Bergers 13,  Agnès Noël 14,  Paul M Grandgenett 15,  Michael A Hollingsworth 15,  David Tuveson 16,  Nancy Boudreau 2,  Jacqueline Bromberg 17,  David Kelsen 18,  David R Jones 19,  Laura Santambrogio 20,  Melody Y Zeng 7,  Virginia Pascual 7,  Han Sang Kim 21,  Christopher E Mason 3,  Haiying Zhang 22,  Irina R Matei 23,  David Lyden 24
Affiliations

Affiliations

  • 1 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
  • 2 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 3 Department of Physiology, Biophysics, and Systems Biology, Weill Cornell Medicine, New York, NY, USA.
  • 4 Department of Systems Biology, Columbia University, New York, NY, USA.
  • 5 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Respiratory Medicine, Juntendo University, Tokyo, Japan.
  • 6 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
  • 7 Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
  • 8 Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
  • 9 Proteomics Resource Center, The Rockefeller University, New York, NY 10065, USA.
  • 10 Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 11 Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12 Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
  • 13 Laboratory of Tumor Microenvironment and Therapeutic Resistance, KU Leuven, Leuven, Belgium.
  • 14 Laboratory of Biology of Tumor and Development, Université de Liège, Liège, Belgium.
  • 15 Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
  • 16 Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY 11724, USA.
  • 17 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 18 Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 19 Thoracic Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 20 Department of Radiation Oncology, Weill Cornell School of Medicine, New York, NY, USA.
  • 21 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA; Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
  • 22 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: [email protected].
  • 23 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: [email protected].
  • 24 Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. Electronic address: [email protected].
PMID: 42066762 DOI: 10.1016/j.ccell.2026.03.023
Abstract

Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and Cancer. ATEV-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EVDNA), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by ATEVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EVDNA encoding APP genes. DNase treatment removes most AT-EVDNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, ATEVs hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by ATEVs that boosts APP and anti-tumor immunity while limiting autoimmunity.

Keywords

EV(DNA); acellular immunotherapy; activated T cell-derived EVs; antigen presentation; gene transfer.

Figures
Products
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    Product Name
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  • HY-100895
    TYK2 Inhibitor
    JAK