Manganese‐CpG Nanocomposite Integrates ROS‐Induced Cell Apoptosis and STING‐Activated and Adjuvant‐Augmented Immune Responses for Tumor Elimination and Prevention

Abstract Chemodynamic therapy (CDT) based on Fenton‐like reaction possesses great potential for anticancer therapy with high efficiency and specificity. However, CDT still suffers low therapeutic efficiency due to intratumoral insufficient H 2 O 2 or unfavorable tumor microenvironment. To enhance tumor treatment and in particular prevent tumor recurrence, the combined strategies with CDT are essentially needed. Herein, a nanocomposite based on Mn 2+ and cytosine‐phosphate‐guanine oligonucleotides (CpG ODNs) (MnCpGPNCs) is constructed to combine CDT with immunostimulating responses by exploiting Mn 2+ ‐induced CDT and Mn 2+ /CpG ODNs‐coinduced immunotherapy against mouse colon tumor cells. Specifically, MnCpGPNCs efficiently deliver and sensitively release Mn 2+ in tumor cells to trigger Fenton‐like reaction, causing cell apoptosis. Importantly, Mn 2+ also promotes the stimulator of interferon genes pathway to increase the production of type I interferons, thus increasing cytotoxic T lymphocyte infiltration, dendritic cell maturation, and proinflammatory cytokine secretion. Furthermore, CpG ODNs serve as immune adjuvant enhanced the antigen presentation and immune‐eliciting potency. The combination of Mn 2+ ‐based CDT with augmented immunotherapy efficiently inhibits the primary/distance tumors and prevents tumorigenesis. Overall, this newly developed metal‐CpG system demonstrates a paradigm to expand chemodynamic agents as immunotherapy boosters to complement current treatments for tumor elimination and prevention.