A bifunctional nanomodulator for boosting CpG-mediated cancer immunotherapy

Unmethylated cytosine-phosphate-guanine (CpG) oligonucleotides (ODNs) possess high immunostimulatory activity and represent attractive tools for cancer treatment. However, their success in eliminating large solid tumors was hampered by the immunosuppressive tumor microenvironment. Herein, we report that the design of a novel MnO₂-CpG-silver nanoclusters (AgNCs)-doxorubicin (DOX) conjugate for enhanced cancer immunotherapy, in which MnO₂ nanosheets function as unique supports to integrate the chemotherapy drug DOX and the immunotherapeutic agent CpG-AgNCs. Importantly, DOX could be conjugated with MnO₂ nanosheets through π-π interactions to serve as a bifunctional modulator of the tumor microenvironment to activate a tumor-specific immune response by inducing immunogenic cell death, and reverse the immunosuppressive tumor microenvironment via abrogating the immune-suppressive activity of regulatory T cells, both of which would greatly improve the immune response of CpG-AgNCs. In this way, the T-cell immune responses of CpG-AgNCs which are linked to MnO₂ nanosheets were significantly enhanced and could exhibit remarkable antitumor activity against large solid tumors. Our study may guide the rational design of immunotherapeutic boosters for improving cancer treatment.