biostudies-literatureWang KNational Natural Science Foundation of ChinaNational Natural Science Foundation of China (National Science Foundation of China)334https://www.ebi.ac.uk/biostudies/studies/S-EPMC12508477biostudies-literatureUnknown10(1)Alpha hemolysin, a pore-forming toxin from Staphylococcus aureus, is a critical virulence factor for bacteria. Previous studies have demonstrated that the Hla mutant H35A (Hla_H35A) serves as a potent carrier protein for subunit vaccines, yet its immunomodulatory mechanisms remain incompletely understood. Here, we demonstrate that the Hla_H35A fusion enhances vaccine efficacy by targeting A Disintegrin and Metalloproteinase 10 (ADAM10) on dendritic cells (DCs), thereby activating the ADAM10-Notch signaling axis. Using the candidate antigen PA0833 from Pseudomonas aeruginosa as a model, we show that the Hla_H35A-PA0833 fusion protein (HPF) significantly augments antigen uptake, DC maturation, and Notch-dependent transcriptional programs, particularly in conventSignal transduction and targeted therapyAlpha hemolysin enhances the immune response by modulating dendritic cell differentiation via ADAM10-Notch signaling.PMC125084773230077832170938Jing HLiao YGou QXia ZYan PZhang JSun TZhao ZWang KLiao JChen ZZhang XZou QLiang MYu TZeng HTang YYu XYuan YfalseAlpha hemolysin enhances the immune response by modulating dendritic cell differentiation via ADAM10-Notch signaling.Alpha hemolysin, a pore-forming toxin from Staphylococcus aureus, is a critical virulence factor for bacteria. Previous studies have demonstrated that the Hla mutant H35A (Hla_H35A) serves as a potent carrier protein for subunit vaccines, yet its immunomodulatory mechanisms remain incompletely understood. Here, we demonstrate that the Hla_H35A fusion enhances vaccine efficacy by targeting A Disintegrin and Metalloproteinase 10 (ADAM10) on dendritic cells (DCs), thereby activating the ADAM10-Notch signaling axis. Using the candidate antigen PA0833 from Pseudomonas aeruginosa as a model, we show that the Hla_H35A-PA0833 fusion protein (HPF) significantly augments antigen uptake, DC maturation, and Notch-dependent transcriptional programs, particularly in convent2025-01-01T00:00:00Z2025 Oct2026-06-04T09:15:51.447Z2026-06-01T03:06:44.801ZS-EPMC125084774106245510.1038/s41392-025-02432-3