Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy via Enhancing Innate Immunity

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are essential components of the innate immune sensors to cytosolic DNA and elicit type I interferon (IFN). Recent studies have revealed that manganese (Mn) can enhance cGAS and STING activation to viral infection. However, the role of Mn in antitumor immunity has not been explored. Here, we designed a nanoactivator, which can induce the presence of DNA in cytoplasm and simultaneously elevate Mn²⁺ accumulation within tumor cells. In detail, amorphous porous manganese phosphate (APMP) NPs that are highly responsive to tumor microenvironment were employed to construct doxorubicin (DOX)-loaded and phospholipid (PL)-coated hybrid nanoparticles (PL/APMP-DOX NPs). PL/APMP-DOX NPs were stably maintained during systemic circulation, but triggered to release DOX for inducing DNA damage and Mn²⁺ to augment cGAS/STING activity. We found that PL/APMP-DOX NPs with superior tumor-targeting capacity boosted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. Furthermore, the NPs increased production of type I IFN and secretion of pro-inflammatory cytokines (for example, TNF-α and IL-6). Consequently, PL/APMP-DOX NPs exhibited excellent antitumor efficacy and prolonged the lifespan of the tumor-bearing mice. Collectively, we developed a PL-decorated Mn-based hybrid nanoactivator to intensify immune activation and that might provide therapeutic potential for caner immunotherapy.