Controlled release of manganese and magnesium ions by microsphere-encapsulated hydrogel enhances cancer immunotherapy

Despite the considerable potential of immune checkpoint blockade (ICB) therapy in treating various cancer types, it faces several challenges, of which the constrained objective response rate and relatively short duration of response observed in patients with cancer are the most important. This study introduces an injectable temperature-sensitive hydrogel, Pluronic F-127 (PF-127)@MnCl₂/ alginate microspheres (ALG-MS)@MgCl₂, that enhances the therapeutic efficacy of programmed cell death-ligand 1 (PD-L1) in cancer cells. The hydrogel material used in this study facilitated the rapid release of a significant amount of manganese ions (Mn²⁺) and the gradual and sustained release of magnesium ions (Mg²⁺) within the tumor microenvironment. This staged release profile promotes an immune microenvironment conducive to the cytotoxicity of CD8⁺ T cells and natural killer cells, thereby enhancing the efficacy of ICB therapy. Furthermore, the PF-127@MnCl₂/ALG-MS@MgCl₂ composite hydrogel exhibits the ability to convert drug-resistant tumor ("cold tumor") with a low PD-L1 response to a "hot tumor" with a high PD-L1 response. In summary, the PF-127@MnCl₂/ALG-MS@MgCl₂ hydrogel manipulates the immune microenvironment through the precise discharge of Mg²⁺ and Mn²⁺, thus, augmenting the efficacy of ICB therapy.