Construction of novel magnetic systems for cancer immunotherapy via cancer-immunity cycle circuits.

The tumor microenvironment (TME) is enriched with immunosuppressive factors that inhibit the recruitment and activation of dendritic cells (DCs), thereby reducing the efficacy of tumor immunotherapy. To address this challenge, we propose an innovative strategy involving the sequential administration of MCM magnetic nanoparticles carrying PROTAC drugs (MCM/ARV) and M-BMDCs in the TEM. This approach not only replenishes DCs in the TEM, but also increases antigen uptake through the attraction between the magnetic particles and promotes DC activation and antigen presentation, thus continuously enhancing the tumor immune cycle. MCM nanoparticles (magnetic nanoclusters coated with calcium-doped manganese carbonate) efficiently load the tumor-targeting drug PROTAC (ARV-825), enhancing its bioavailability, leading to specific degradation of BRD4 in tumor cells, and releasing a large number of tumor-associated antigens. These antigens were captured by MCM nanoparticles to construct magnetized tumor vaccines. Magnetic M-BMDCs introduced at the tumor site are attracted to these magnetized vaccines, resulting in a significant increase in antigen uptake and activation of DCs, significantly enhancing the tumor immune cycle. This co-administration strategy of magnetized vaccines and magnetized BMDCs provides a unique combination therapy for reversing immunosuppressive TEM and enhancing the efficacy of tumor immunotherapy.