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, the 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 Mn2+. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn2+ promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn2+ coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN–Mn2+ particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy. The stimulation of interferon genes (STING) pathway with STING agonists such as cyclic dinucleotides (CDNs) has emerged as a promising immunotherapeutic approach. Here, the authors show that Mn2+ can amplify the STING-promoted anti-tumour immune response in challenging murine tumour models by coordinating with CDNs and self-assembling into nanoparticles that can be delivered locally and systemically.