Robust and Sustained\nSTING Pathway Activation via\nHydrogel-Based In Situ Vaccination for Cancer Immunotherapy

The stimulator of interferon genes (STING) pathway is\ncrucial for\ntumor immunity, leading to the exploration of STING agonists as potential\nimmunotherapy adjuvants. However, their clinical application faces\nobstacles including poor pharmacokinetics, transient activation, and\nan immunosuppressive tumor microenvironment (TME). Addressing these\nlimitations, our study aims to develop an injectable silk fibroin\nhydrogel-based in situ vaccine. It incorporates a nanoscale STING\nagonist, an immunogenic cell death (ICD) inducer, and an immunomodulator\nto ensure their controlled and sustained release. cGAMP nanoparticles\n(cGAMPnps) with a core–shell structure ensure optimal delivery\nof cGAMP to dendritic cells (DCs), thereby activating the STING pathway\nand fostering DC maturation. ICD-associated damage-associated molecular\npatterns amplify and prolong STING activation via enhanced type I\nIFN and other inflammatory pathways, along with delayed degradation\nof cGAMP and STING. Furthermore, the STING-driven vascular normalization\nby cGAMPnps and ICD, in conjunction with immunomodulators like antiprogrammed\ncell death protein 1 antibody (anti-PD-1 Ab) or OX40 ligand (OX40L),\neffectively remodels the immunosuppressive TME. This in situ gel vaccine,\nwhen used independently or with surgery as neoadjuvant/adjuvant immunotherapy,\nenhances DC and CD8<sup>+</sup> T-cell activation, suppressing tumor\nprogression and recurrence across various immunologically cold tumor\nmodels. It revolutionizes the application of STING agonists in cancer\nimmunotherapy, offering substantial promise for improving outcomes\nacross a broad spectrum of malignancies.