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

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.