EV-DNA-Mediated Immune Communication: A Barrier to Metastasis

The Shmunis School of Biomedicine and Cancer Research

Shmunis weekly school seminar

EV-DNA-Mediated Immune Communication: A Barrier to Metastasis

Tuesday, November 4th, 2025, 12:15
Sherman building room 03
Light refreshments will be served at 12:00

Dr. Inbal Wortzel
Dep. of Cancer Biology & Immunology
Gray Faculty of Medicine
Tel-Aviv University
Zuckerman Faculty Scholar

Extracellular vesicles (EVs) are emerging as critical mediators of tumor-host communication, yet the role of EV-associated DNA (EV-DNA) in metastasis has remained unclear. We recently uncovered that tumor-derived EV-DNA is predominantly surface-bound and organized as a unique chromatin structure, enriched in cleaved and post-translationally modified histones. Using genome-wide CRISPR screening, we identified key immune developmental genes, including APAF1 and NCF1, as essential regulators of EV-DNA packaging. Functionally, EV-DNA uptake by Kupffer cells in the pre-metastatic liver triggers DNA damage responses, reprograms cytokine secretion, and promotes the formation of tertiary lymphoid structures, collectively suppressing metastatic colonization. Conversely, loss of EV-DNA packaging facilitates an immune-evasive microenvironment and accelerates metastasis. Analyses of colorectal and breast cancer models, as well as patient tumor-derived EVs, suggest that high EV-DNA levels may serve as a biomarker for reduced metastatic risk. Together, these findings reveal EV-DNA as both a mechanistic driver of antitumor immunity and a potential prognostic tool in breast and colorectal cancer.