Over the past decade, researchers have been dedicated to developing more effective and long-lasting cancer treatments. As part of this effort, Stimulator of Interfron Genes activation (STING agonism) has emerged as a promising approach to utilize the Immune system in fighting tumors throughout the body.

Despite its potential, there are significant challenges to overcome before STING agonism can be effectively used as a treatment. One such challenge is the intravenous administration of STING agonist drugs, which often proves ineffective due to issues with drug stability and immune cell uptake.

Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, has tackled these challenges head-on by designing stimuli-responsive nanoparticle structures that allow STING agonist drugs to be released specifically within the target cells. In a recently published paper in Nature Nanotechnology, the team of researchers revealed that these stabilized nanoformulations not only eliminated active tumors in mice, but also trained their immune systems to detect and eliminate future tumors.

Senior author Dr. Natalie Artzi, a principal investigator in the Brigham’s Department of Medicine, explained, “Our aim is to utilize STING agonism to educate the immune system to recognize cancer cells as invaders. This requires the creation of stable and potent nanostructures that ensure STING reaches the appropriate organs and cells.”

Lead author Dr. Pere Dosta Pons, an instructor in the Brigham’s Department of Medicine, emphasized the novelty of their approach, stating, “We are not only teaching the immune system to target and eliminate cancer cells, but also to develop immune memory and prevent cancer recurrence.”

STING agonism involves activating a protein called the stimulator of interferon genes (STING), which alerts the immune system to the presence of invaders. When the body is infected with a virus or bacteria, cytosolic cyclic dinucleotides (CDN) molecules attach themselves to STING, initiating the production of proinflammatory cytokines. These cytokines then activate immune cells such as natural killer cells, macrophages, and T-cells, recruiting them to the infection site to clear the infection.

Cancer cells evade this STING pathway by disguising themselves as normal cells. Researchers have been exploring methods to teach the immune system to recognize and attack cancer cells by delivering STING agonists to immune cells in the tumor microenvironments and tumor-draining lymph nodes.

In their recent study, the team from Brigham Hospital developed a new nanoparticle structure that more effectively transports CDN molecules into immune cells. This structure directly connects lab-produced CDNs to nanoparticles made of poly(beta amino esters) (pBAEs), resulting in a compound that is more stable and potent when injected into the body. The nanoparticle structure acts as a carrier, delivering the CDN messengers directly to tumors and releasing them only within the target cells.

To assess the effectiveness of their approach, the team administered CDN-nanoparticle (CDN-NP) compounds to mice with melanoma, colon cancer, and breast cancer tumors. They observed that their CDN-nanostructures were taken up by immune cells in the tumor microenvironment and Secondary Lymphoid Organs, providing mice with long-term immunity against future tumors. When these mice were reintroduced to tumors 60 days after the initial treatment, they were able to reject the tumors on their own.

The researchers also established a set of design principles that must be considered when delivering immune therapy, including the role of secondary lymphoid organs in dictating therapeutic outcomes. They demonstrated the crucial role of the spleen in training the immune system to generate immune memory.

Studies like this not only contribute to our understanding of cancer and immunology, but also highlight the potential for improving gene therapy delivery systems for treating diseases such as cancer.

Dr. Artzi underscored the significance of the work, stating, “Our research delves into the fundamental interaction between the immune system and cancer through the use of novel, stable, and potent nanostructures. Furthermore, we have shown that targeting secondary lymphoid organs, such as the spleen, is critical in generating long-lasting anti-tumor responses, which has important implications for immunotherapy delivery.”

 

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