The Multiomics Landscape of Plasma-Derived Small Extracellular Vesicles during the Development of HPV+ Cervical Cancer

The transition from HPV infection to cervical cancer (CC) remains unclear, especially concerning small extracellular vesicles (sEVs). We analyzed plasma-sEVs from HPV-negative individuals (HPVN-sEVs), HPV-positive individuals (HPVP-sEVs), and HPV-positive CC patients (HPVC-sEVs) via proteomics (n = 5/5/9) and transcriptomics (n = 3/3/4). Multiomics revealed HPVP-sEVs harbor antiviral and pro-inflammatory signals early in infection, whereas HPVC-sEVs shift toward immunosuppression to sustain persistent infection. Specifically, IFITM2─an antiviral gene─was markedly enriched in HPVP-sEVs versus HPVN-sEVs (P < 0.001) and HPVC-sEVs (P = 0.014). Both HPVP-sEVs (P = 0.004) and HPVC-sEVs (P < 0.001) suppressed M2 macrophages, with HPVC-sEVs further reducing IL-6 (HPVN-sEVs, P = 0.005; HPVP-sEVs, P = 0.015). Notably, IFITM2 mRNA and protein levels in plasma-sEVs distinguished HPVP from HPVC patients, showing superior diagnostic accuracy (AUC = 0.833 and 0.822, respectively) over CA-125. These findings underscore sEVs’ dynamic role in HPV-driven carcinogenesis and their potential as noninvasive biomarkers for CC diagnosis.