Targeted immunomodulation with CD44-targeting nanovaccine enhances antitumor immunity in melanoma through TLR7/8 and TLR3 agonists.

Cancer is a leading cause of death. Melanoma, a highly metastatic and aggressive skin cancer, has seen rising mortality rates despite advancements in chemotherapy. Recently, immunotherapy has emerged as a promising approach to address the limitations of conventional treatments. This study developed a tumor microenvironment-sensitive nanoparticle (HA-NPs) for a nanovaccine. The nanoparticle is composed of CD44-targeting hyaluronic acid, pH-responsive ammonium bicarbonate, resiquimod (a TLR-7/8 agonist), Poly I:C (a TLR-3 agonist), and the tumor-specific antigen ovalbumin (OVA), ensuring a targeted and effective approach to treatment. The combination of dual adjuvants (R848 and Poly I:C) enhances the immune response, while ammonium bicarbonate ensures pH sensitivity, improving targeted delivery and effectiveness in the tumor microenvironment. The antitumor efficacy of the nanovaccine was evaluated in a highly immunogenic, OVA-expressing B16F10 murine tumor model. The intratumoral administration of HA-NPs harnessed the adjuvant potency of R848 and Poly IC, thus enhancing antitumor immunity. Additionally, immune cell profiling revealed elevated levels of mature dendritic cells in vitro, as well as CD8+ T cells, and reduced levels of tumor-associated immunosuppressive cells (TAICs), such as regulatory T (Treg) cells, within the tumors. Overall, this study demonstrated the potential of HA-NPs to elicit antitumor solid immunity through the targeted immunomodulation of antigen-presenting cells and the reduction of tumor-associated immune cells (TAICs), offering a promising avenue for melanoma treatment.