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.