Amplifying STING activation by cyclic dinucleotide–manganese particles for local and systemic cancer metalloimmunotherapy

Abstract

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.

Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion

“…Recently, we generated a new HNSCC murine model that bears over 90% similarity to human tobacco-associated cancers, NOOC1. 23 To validate our findings, we generated Ifnar1 -deficient NOOC1 cells ( Figure 2e ). We found that a defect in Ifnar1 expression resulted in compromised expression of Mx1, Isg54 , and Isg15 in response to Ifn-β ( Figure 2f-h ).…”

Metallic Nanoparticle-Mediated Immune Cell Regulation and Advanced Cancer Immunotherapy

“…Moon et al have reported recently that Mn 2+ coordinated CDN NPs amplified the STING activation compared to other metals. The combination of Mn 2+ and STING agonists enhanced the T cells population in mice and suppressed the tumor growth [96].…”

“…Similarly, Moon et al have reported that Mn 2+ coordinated with cyclic dinucleotide (CDN) STING agonist self-assembled into the nanoparticle and enhanced STING delivery [96]. Manganese MNPs augmented STING activity 12 to 77-fold more in human STING haplotypes and promoted STING independent pathways [96].…”

“…Mn 2+ sufficient mice promoted a greater DC maturation, macrophage, and NK cell activation and increased CD8 + memory T cells in mice compared to Mn 2+ insufficient mice [95]. Similarly, Moon et al have reported that Mn 2+ coordinated with cyclic dinucleotide (CDN) STING agonist self-assembled into the nanoparticle and enhanced STING delivery [96]. Manganese MNPs augmented STING activity 12 to 77-fold more in human STING haplotypes and promoted STING independent pathways [96].…”

Targeting the innate immune system with nanoparticles for cancer immunotherapy

“…Administration of CMP 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. 126 Other studies have also developed mesoporous silica nanoparticles (MSN) to load STING agonists to reprogram the tumor-resident innate immune cells and overcome the immunosuppressive tumor microenvironment. [127][128][129] One study has indicated that STING agonist CDA delivered via biodegradable mesoporous silica nanoparticles (bMSN) potently activate innate and adaptive immune cells, leading to strong antitumor efficacy and prolonged animal survival in murine models of melanoma.…”