Bivalent Se nanovaccines targeting both tumor cells and cancer-associated fibroblast for potent anti-desmoplastic tumor immunotherapy.

Current cancer vaccines mainly focusing on inducing cancer cells-specific immune responses showed very limited efficacy because of the extremely complicated tumor microenvironments. Herein, we facilely construct Se nanoadjuvant-based bivalent DNA nanovaccines targeting both melanoma and cancer-associated fibroblast (CAF), based on the crucial roles of CAF in desmoplastic tumors and Se element in immune regulations. Intriguingly, the bivalent Se nanovaccines significantly induce robust bi-specific immune responses such as more activated macrophages, higher population of OVA+FAP+CD8+ T lymphocytes with enhanced multi-functionality, more germinal center B cells and short-lived plasma cells to generate bi-specific antibodies of high titers via triggering multiple Toll-like receptors (e.g., TLR3, TLR9) signaling pathways, enhancing antigen cross-presentation and relieving ROS stress. More importantly, bivalent nanovaccines efficiently induce robust immunological memory such as memory B cells, long-lived plasma cells, central and effector memory and tissue-resident memory T lymphocytes in spleen and skin. The bivalent nanovaccines as both prophylactic and therapeutic modalities also significantly inhibit melanoma progressions via specifically damaging both B16-OVA and CAF, and shaping tumor immuno-microenvironments like inducing more anti-tumor immune cells (e.g., NK, NKT, cytotoxic T cells) and reducing myeloid derived suppressor cells and tumor-associated macrophages. This study provides unique Se nanoadjuvant platform for the next-generation vaccines against desmoplastic tumors.