Extracellular vesicles derived from mature dendritic cells loaded with cDC1-specific chemokine XCL1 combined with chemotherapy-induced ICD for the treatment of castration-resistant prostate cancer.

BACKGROUND: Dendritic cells (DCs) derived extracellular vesicles represent a promising vehicle for the activation of adaptive immunity, demonstrating significant potential in the development of cancer nanovaccines. The aim of this study was to evaluate the antitumor efficacy of a functional DCs-derived extracellular vesicles in castration-resistant prostate cancer. METHODS: A pre-modification strategy was employed to overexpress XCL1 in dendritic cells, enabling their extracellular vesicles to highly express XCL1 protein. In vitro experiments, prostate cancer-bearing mouse models, and OVA-expressing prostate cancer mouse models demonstrated that dendritic cells efficiently internalize extracellular vesicles derived from XCL1-overexpressing mature dendritic cells (DEX(XCL1)), thereby enhancing the chemotaxis, activation, and antigen-presenting capacity of cDC1 cells. When combined with the immunogenic cell death effect induced by cisplatin, this approach significantly increased the number and cytotoxic activity of CD8(+) T cells, improved the tumor microenvironment, and effectively suppressed prostate cancer tumor growth. RESULTS: The coding sequence of XCL1 successfully inserted upstream of the PDGFR transmembrane domain and transfected into dendritic cells, enabling their extracellular vesicles to highly express XCL1 protein. Extracellular vesicles derived from XCL1-overexpressing mature dendritic cells not only exhibited high XCL1 expression, but were also enriched with chemokine receptor CCR7 and MHC I molecules on their surface. This nanovaccines enhanced the uptake of extracellular vesicles by dendritic cells, recruited cDC1 cells within the tumor tissue, and significantly improved their antigen-presenting capacity. When combined with the immunogenic cell death effect induced by cisplatin, which generates a large amount of tumor-associated antigen STEAP1, this strategy effectively enhanced the proliferation and cytotoxic activity of CD8(+)T cells. Moreover, it reduced the proportion of regulatory T cells and immunosuppressive factors, thereby reshaping the tumor immune microenvironment. This approach effectively inhibited tumor growth in mice and prolonged their survival. These findings demonstrate the strong synergistic effects of the nanovaccines and cisplatin in promoting antitumor immunity. CONCLUSIONS: A novel nanovaccines induces potent antitumor immune responses and, in combination with the chemotherapeutic agent cisplatin, effectively remodels the tumor immune microenvironment. This approach offers a new strategy and preclinical evidence for the immunotherapy of "cold tumors" prostate cancer.