Researchers at the University of Michigan (U-M) School of Pharmacy and the Rogel Cancer Center took a different approach to boosting the STING pathway. The team observed that adding the nutritional metal ion manganese to STING agonists boosted STING’s tumor-fighting capability.

Their findings are published in the journal Nature Nanotechnology in a paper titled, “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,” the researchers wrote. “Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy.”

The researchers observed that adding the nutritional metal ion manganese to STING agonists boosted STING’s tumor-fighting capability up to 77-fold, compared to STING agonists used alone, explained James Moon, the J.G. Searle professor of pharmaceutical sciences and of biomedical engineering.

Most STING agonists must be delivered directly into the tumor, but this isn’t suitable for metastatic cancers, a major cause of mortality. To develop a STING agonist for intravenous administration, the researchers coated these nanocrystals with a lipid layer (similar to those found in mRNA COVID-19 vaccines), resulting in a nanoparticle system called CMP.

“CMP significantly increases cellular uptake of STING agonists, and together with manganese, CMP triggers robust STING activation, turns a cold tumor into a hot tumor, and eliminates cancer, including those that are completely resistant to immune checkpoint inhibitors, the most widely used cancer immunotherapy,” said Xiaoqi “Kevin” Sun, a U-M graduate student in pharmacy and first author on the paper.

The team’s research is the first to demonstrate nanoparticles delivering STING agonists and metal ions can be developed for intravenous cancer immunotherapy, and this may pave the way for further cancer immunotherapy treatments.

“The 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, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy,” wrote the researchers.

The team is currently working to test the safety and efficacy of CMP in large animals. “We anticipate that we will be able to initiate a Phase I clinical study to examine the efficacy of CMP in cancer patients in the near future,” Moon said.

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