Multivalent Metal–Nucleotide Nanoagonists Amplify Innate Immune Activation for Cancer Metalloimmunotherapy

Metalloimmunotherapy represents a new paradigm in cancer immunotherapy by leveraging the immune-modulatory functions of metal ions, either alone or in combination with agonists. However, the low bioavailability of free metal ions and agonists limits robust stimulation of antitumor immune responses. Here we developed multivalent metal-nucleotide nanoagonists (Mn-MNAs) through aqueous coordination of multiple nucleotide-based innate immune agonists with Fe²⁺ and Mn²⁺, which not only enhanced the stability and cellular uptake of the agonists but also amplified the antitumor immunity by concurrently activating the stimulator of interferon genes (STING) and toll-like receptor 9 (TLR9) pathways. Intratumoral injection of Mn-MNAs significantly inhibited tumor growth and fostered an immune-supportive tumor microenvironment in the CT26 tumor model. Intravenous administration of Mn-MNAs achieved remarkable therapeutic efficacy in the B16F10 melanoma model, which was further enhanced upon combination with a checkpoint blockade. Overall, multivalent nanoagonists open new avenues for cancer metalloimmunotherapy.