Construction of In Situ Personalized Cancer Vaccines by Bioorthogonal Catalytic Microneedles for Augmented Melanoma Immunotherapy.

In situ personalized tumor vaccines are produced directly at the primary tumor site by killing cancer cells and stimulating immune cells, they are effective against individuals and bypass the complexity and high cost of in vitro vaccine production. However, their clinical application is hindered by insufficient efficiency in inducing immunogenic cancer cell death (ICD) and systemic inflammation caused by immune adjuvants. Here, personalized cancer vaccines are constructed in situ for melanoma immunotherapy based on bioorthogonal catalytic microneedles, which enable the catalytic release of prodrugs at tumor sites and mediate strong ICD and an enhanced tumor immune response while avoiding systemic immune storms and toxic side effects. By incorporating TiO2 nanosheets supported Pd into swellable microneedles, the bioorthogonal microneedles are constructed to catalyze the depropargylation reaction of doxorubicin (DOX) prodrug and imiquimod (IMQ) prodrug in situ. The activated DOX at subcutaneous tumor sites induced strong ICD and released tumor-associated antigens. Concurrently, the activated IMQ acts as a Toll-like receptor (TLR7) agonist, enhancing the anti-tumor immune response. In vivo experiments demonstrate that this immunotherapy achieves ≈97% inhibition of primary tumors and effectively inhibits untreated distant tumors (≈94% inhibition) and lung metastasis (≈92% inhibition).