{
  "abstract": "Background Prostate cancer (PCa) is a prevalent malignancy with limited treatment options for advanced stages. Oncolytic virotherapy represents a promising immunotherapeutic approach, but its efficacy and underlying mechanisms in PCa, particularly concerning immune checkpoint regulation, remain unclear.Methods The antitumor effects of the oncolytic virus oncolytic herpes simplex virus type 2 (OH2) were evaluated in PCa cell lines and mouse models. Transcriptome sequencing, western blot, chromatin immunoprecipitation-sequencing-quantitative PCR, and flow cytometry were employed to investigate the mechanism of programmed death 1 ligand 1 (PD-L1) regulation. A targeted delivery system, reactive oxygen species (ROS)-responsive aptamer-conjugated anti-prostate-specific membrane antigen (PSMA) extracellular vesicles (RRA-AP-EVs), was engineered from anti-PSMA single chain variable fragment (scFv)-modified extracellular vesicles and an ROS-responsive PD-L1 blocking aptamer. OH2 was loaded via membrane extrusion, and the resulting OH2@RRA-AP-EVs were tested for targeting and therapeutic efficacy following intravenous administration.Results OH2 effectively killed PCa cells but simultaneously activated the IKK/I-κBα/p65 pathway, leading to PD-L1 upregulation and adaptive immune resistance. While combining OH2 with anti-PD-L1 improved outcomes, clinical translation was hindered by delivery challenges. The novel OH2@RRA-AP-EVs system demonstrated precise tumor targeting and ROS-triggered local PD-L1 blockade. Intravenous injection of OH2@RRA-AP-EVs showed superior tumor control (inhibiting tumor growth by 70% vs free OH2) and enhanced CD8+T cell infiltration and function compared with free OH2 (greater than twofold increase in intratumoral CD8+T cell infiltration along with over twofold upregulation of key effector molecules).Conclusion This study identifies a mechanism of OH2-induced PD-L1 expression in PCa and provides a versatile, targeted delivery platform that enables effective intravenous viro-immunotherapy, overcoming key translational barriers.",
  "authors": [
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Jin-Zhou Xu"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Ye An"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Jian-Xuan Sun"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Yi-Fan Xiong"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China",
        "Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Science, The University of Texas Southwestern Medical Center, Dallas, Texas, USA"
      ],
      "name": "Chen-Qian Liu"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Si-Han Zhang"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Zhi-Yu Xia"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Jia Hu"
    },
    {
      "affiliations": [
        "Binhui Biopharmaceutical Co Ltd, Wuhan, China"
      ],
      "name": "Zi-Yi Zhang"
    },
    {
      "affiliations": [
        "National \"111\" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hebei University of Technology, Wuhan, China"
      ],
      "name": "Ci-Xiang Guo"
    },
    {
      "affiliations": [
        "Binhui Biopharmaceutical Co Ltd, Wuhan, China",
        "National \"111\" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Center of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hebei University of Technology, Wuhan, China"
      ],
      "name": "Bin-Lei Liu"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Wei Guan"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Shao-Gang Wang"
    },
    {
      "affiliations": [
        "Department and Institute of Urology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China"
      ],
      "name": "Qi-Dong Xia"
    }
  ],
  "title": "Oncolytic virus OH2 induces PD-L1 upregulation via NF-κB signaling and synergizes with anti-PD-L1 therapy in prostate cancer through a targeted extracellular vesicle delivery system",
  "uid": "d3eea4e7-7b4f-5962-b037-a5289a213571"
}