Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity PMID: 42066762

ADC Targets in Oncology

2026-04-10

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

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].

Abstract

Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (AT_EVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and Cancer. AT_EV-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EV_DNA), 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 AT_EVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EV_DNA encoding APP genes. DNase treatment removes most AT-EV_DNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, AT_EVs 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 AT_EVs that boosts APP and anti-tumor immunity while limiting autoimmunity.

Keywords

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