Researchers at the Massachusetts Institute of Technology (MIT) have discovered a method to activate an immune pathway in tumors, potentially leading to their destruction. By stimulating cancer cells to produce a molecule that engages nearby immune cells, the team has found a way to encourage tumors to trigger their own demise. This innovative approach leverages the cGAS-STING pathway and shows promise when combined with existing immunotherapy drugs known as checkpoint blockade inhibitors.
The study, conducted on mice, revealed that simultaneously activating this pathway and administering checkpoint inhibitors significantly controlled tumor growth. The researchers utilized messenger RNA (mRNA) to turn on the cGAS-STING pathway in immune cells, which may mitigate the side effects associated with delivering high doses of a STING activator. This strategy capitalizes on a natural biological process, potentially paving the way for new treatments in human patients.
Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science and an associate professor at Harvard Medical School, emphasized the significance of their findings. “Our approach harnesses the tumor’s own machinery to produce immune-stimulating molecules, creating a powerful antitumor response,” she stated. By enhancing cGAS levels inside cancer cells, the researchers improved delivery efficiency, which stimulates the natural production of cGAMP, an immune-activating molecule.
The cGAS-STING pathway plays a crucial role in triggering immune responses. When activated, it initiates the production of type one interferons, cytokines that stimulate immune cells to recognize and attack tumors. Although previous attempts to artificially stimulate this pathway using STING agonists have shown promise in animal models, clinical trials have faced challenges due to side effects from high doses.
During the research, lead author Alexander Cryer, a visiting scholar at IMES, noted the potential of leveraging the body’s existing processes. He remarked, “Once I saw that cancer cells produce this molecule, I thought: Maybe there’s a way to take this process and supercharge it.” The production of cGAMP is catalyzed by the enzyme cGAS, which detects double-stranded DNA in cells—often a sign of cancer or infection.
To activate STING in immune cells, the researchers designed a method to deliver mRNA encoding cGAS directly to tumor cells. As these cells divide rapidly and inaccurately, they tend to accumulate more double-stranded DNA fragments than healthy cells. This allows tumor cells to secrete cGAMP into the tumor microenvironment, activating neighboring immune cells.
In their experiments with a mouse model of melanoma, the researchers evaluated the effectiveness of their novel strategy in killing cancer cells. They injected mRNA encoding cGAS, encapsulated in lipid nanoparticles, into tumors. Mice receiving this treatment alone, as well as those treated with only a checkpoint blockade inhibitor, exhibited significant tumor growth reduction. However, the most impressive results emerged from the group receiving both treatments, where tumors were completely eradicated in 30% of the mice.
Analysis of the immune responses indicated that the mRNA treatment stimulated the production of interferons and various immune-signaling molecules. A diverse array of immune cells, including macrophages and dendritic cells, were activated, subsequently stimulating T cells to attack cancer cells. Remarkably, the researchers achieved these responses with a small dose of cancer-cell-produced cGAMP, addressing a key challenge of using cGAMP as a standalone therapy, which typically requires large doses that can induce inflammation and tissue damage.
Cryer highlighted the advantages of their method, stating, “The side effects of this class of molecule can be pretty severe, and one of the potential advantages of our approach is that you’re able to potentially subvert some toxicity that you might see if you’re giving the free molecules.”
The research team aims to refine their delivery system for potential systemic injection, allowing treatment to be administered more broadly rather than only directly into tumors. They also plan to test this mRNA therapy in conjunction with chemotherapy drugs or radiotherapy, which could enhance the effectiveness of the treatment by increasing the availability of double-stranded DNA to activate cGAMP synthesis.
This groundbreaking study, titled “Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell–generated cGAMP,” was published in the Proceedings of the National Academy of Sciences. The findings offer a promising avenue for developing safer and more effective cancer immunotherapies, bringing researchers one step closer to improving treatment options for patients facing this challenging disease.
