| Autor: |
Cheng SL; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.; International Intercollegiate Ph.D. Program, National Tsing Hua University, Hsinchu 30013, Taiwan., Lee HM; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan., Li CP; Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.; Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei 11217, Taiwan.; Therapeutic and Research Center of Pancreatic Cancer, Veterans General Hospital, Taipei 11217, Taiwan.; School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan., Lin MW; Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310401, Taiwan., Chou MY; Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu 310401, Taiwan., Yen YT; Institute of Translational Medicine and New Drug Development, School of Medicine, China Medical University, Taichung 406040, Taiwan., Wu TH; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan., Lian YC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan., Shih YC; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan., Chiang CS; Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan., Chen TW; Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan.; Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan.; Center for Intelligent Drug Systems and Smart Bio-devices, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan., Wan D; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan., Chen Y; Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.; Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan. |
| Abstrakt: |
The stimulator of interferon genes (STING) pathway is crucial for tumor immunity, leading to the exploration of STING agonists as potential immunotherapy adjuvants. However, their clinical application faces obstacles including poor pharmacokinetics, transient activation, and an immunosuppressive tumor microenvironment (TME). Addressing these limitations, our study aims to develop an injectable silk fibroin hydrogel-based in situ vaccine. It incorporates a nanoscale STING agonist, an immunogenic cell death (ICD) inducer, and an immunomodulator to ensure their controlled and sustained release. cGAMP nanoparticles (cGAMPnps) with a core-shell structure ensure optimal delivery of cGAMP to dendritic cells (DCs), thereby activating the STING pathway and fostering DC maturation. ICD-associated damage-associated molecular patterns amplify and prolong STING activation via enhanced type I IFN and other inflammatory pathways, along with delayed degradation of cGAMP and STING. Furthermore, the STING-driven vascular normalization by cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed cell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L), effectively remodels the immunosuppressive TME. This in situ gel vaccine, when used independently or with surgery as neoadjuvant/adjuvant immunotherapy, enhances DC and CD8 + T-cell activation, suppressing tumor progression and recurrence across various immunologically cold tumor models. It revolutionizes the application of STING agonists in cancer immunotherapy, offering substantial promise for improving outcomes across a broad spectrum of malignancies. |
