Engineered virus-mimicking nanovaccine with lymph node-tumor dual-targeting and STING-activating capacity for robust cancer immunotherapy

Abstract

Cancer vaccines have garnered considerable interest for cancer immunotherapy. However, their effectiveness is limited by inadequate proliferation, activation, and tumor infiltration of cytotoxic T lymphocytes (CTLs). Inspired by the potent immunostimulatory properties of viral components and the exposure of calreticulin during immunogenic cell death (ICD) triggered by viral infections; in this study, we describe cGAMP@vEVs, a virus-mimicking nanovaccine strategy by engineering tumor cell-derived extracellular vesicles through virus infection, which co-load both personalized and broad antigen repertoire as well as multiple immune adjuvants to potently elicit antitumor immunity. We demonstrate that cGAMP@vEVs exhibit both the commendable lymph node-tumor dual-targeting and stimulator of interferon genes (STING) pathway-activating capacity, which drive the proliferation and activation of tumor-specific CD8⁺ T cells in lymph nodes. Simultaneously, cGAMP@vEVs actively accumulate to tumor sites, and ameliorate immunosuppression tumor microenvironment, promoting the spontaneous tumor infiltration of CTLs. The coactivation of the immune response and TME reinitiate the self-sustaining cycle of cancer immunity, therefore efficiently inhibiting tumor progression, metastasis, and recurrence.

Keywords: Dual-targeting; STING agonist; Tumor microenvironment; cancer immunotherapy; cancer vaccine.