Chimeric Exosomes Functionalized with STING Activation for Personalized Glioblastoma Immunotherapy

Abstract

AbstractA critical challenge of existing cancer vaccines is to orchestrate the demands of antigen‐enriched furnishment and optimal antigen‐presentation functionality within antigen‐presenting cells (APCs). Here, a complementary immunotherapeutic strategy is developed using dendritic cell (DC)‐tumor hybrid cell‐derived chimeric exosomes loaded with stimulator of interferon genes (STING) agonists (DT‐Exo‐STING) for maximized tumor‐specific T‐cell immunity. These chimeric carriers are furnished with broad‐spectrum antigen complexes to elicit a robust T‐cell‐mediated inflammatory program through direct self‐presentation and indirect DC‐to‐T immunostimulatory pathway. This chimeric exosome‐assisted delivery strategy possesses the merits versus off‐the‐shelf cyclic dinucleotide (CDN) delivery techniques in both the brilliant tissue‐homing capacity, even across the intractable blood–brain barrier (BBB), and the desired cytosolic entry for enhanced STING‐activating signaling. The improved antigen‐presentation performance with this nanovaccine‐driven STING activation further enhances tumor‐specific T‐cell immunoresponse. Thus, DT‐Exo‐STING reverses immunosuppressive glioblastoma microenvironments to pro‐inflammatory, tumoricidal states, leading to an almost obliteration of intracranial primary lesions. Significantly, an upscaling option that harnesses autologous tumor tissues for personalized DT‐Exo‐STING vaccines increases sensitivity to immune checkpoint blockade (ICB) therapy and exerts systemic immune memory against post‐operative glioma recrudesce. These findings represent an emerging method for glioblastoma immunotherapy, warranting further exploratory development in the clinical realm.