Phosphatidylserine-positive extracellular vesicles for detecting multiple operable cancers

Early cancer detection is critical for reducing mortality. Circulating extracellular vesicles (EVs) offer diagnostic potential, yet reliable tumor-specific biomarkers and detection methods remain elusive. Using lipidomics analysis of EVs from eight cancer and five non-tumorigenic cell lines, we identified phosphatidylserine (PS) as a tumor-specific EV marker. PS-positive EVs were associated with apoptosis induction and tumor burden in both cellular and murine models. We developed PSEV-MultiCancer, a flow cytometry-based blood test detecting PS-positive EVs, achieving an area under the curve (AUC) of 0.932 (95% CI: 0.92-0.94) and a positive detection rate of 84.7% across 12 cancer types in a cohort of 1,869 clinical samples (including 1,269 cancer patients). Sensitivity for early-stage (I-II) cancers reached 74.7% with a specificity of 89.8%. Validation across three independent cohorts yielded AUC values of 0.97, 0.99, and 0.89, respectively. These findings support PSEV-MultiCancer as a promising noninvasive tool for early cancer detection, facilitating timely curative interventions.