Co-delivery of STING and TLR7/8 agonists in antigen-based nanocapsules to dendritic cells enhances CD8+T cell-mediated melanoma remission

Here we demonstrate a novel nanocarrier-based vaccine combining the type I interferon-triggering STING agonist diamidobenzimidazole (diABZI) compound 3 and the well-established TLR7/ 8 agonist resiquimod (R848). Encapsulation of both adjuvants into polymeric nanocapsules enables the simultaneous transport of immunostimulatory molecules with tumor antigens.

The effectiveness of tumor vaccines is still a big challenge because the adjuvants (substances that enhance the body's immune response to an antigen) used are not potent enough. Combining different types of antigens and adjuvants can potentially create a broader immune response against tumors. In this study, we introduce a new nanocarrier (NC)-based vaccine that combines two powerful adjuvants: the STING agonist diamidobenzimidazole (diABZI) compound 3 and the TLR7/8 agonist resiquimod (R848).

By encapsulating both adjuvants in polymeric nanocapsules, we can simultaneously deliver these immune-boosting molecules along with tumor antigens. This co-delivery enhances the stimulation of dendritic cells (DCs), leading to a stronger immune response against tumors. The combined encapsulation of R848 and diABZI resulted in better DC activation and stronger antigen-specific T cell responses compared to using each adjuvant separately or in their soluble forms, both in lab tests and in live animal models. This was evident by the increased expression of immune markers CD80, CD83, and CD86.

Additionally, the dual adjuvant therapy led to higher levels of various pro-inflammatory cytokines and chemokines, and significant T cell proliferation, which contributed to robust tumor regression in a mouse model of B16 melanoma. When administered under the skin, the R848/diABZI-loaded NCs promoted greater infiltration of CD4+ and CD8+ T cells as well as neutrophils into the tumor-draining lymph nodes and tumor tissue. Encapsulating a melanoma-specific antigenic peptide (TRP2) within these adjuvant-loaded NCs slowed down the growth of B16 melanoma tumors and extended the overall survival of the mice.

This new anti-tumor vaccine strategy avoids using structural compounds, increases the antigen load in dendritic cells, uses a fixed combination of antigens and two potent adjuvants, and has the potential to trigger a strong, antigen-specific immune response against cancer.