Amplifying STING Activation by Cyclic Dinucleotide-Manganese Particles for Local and Systemic Cancer Metalloimmunotherapy

Nutritional metal ions play critical roles in many important immune processes. Hence, effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn(2+). We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn(2+) promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn(2+) coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN-Mn(2+) particle, CMP) that effectively delivered STING agonists to immune cells. CMP administered either by local intratumoral or systemic intravenous injection initiated robust anti-tumor immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumor models. Overall, CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.