MIT Researchers Activate Tumor Immune Pathway to Enhance Cancer Treatment

Researchers at the Massachusetts Institute of Technology (MIT) have discovered a method to activate an immune pathway within tumors, potentially leading to their self-destruction. By stimulating cancer cells to produce a molecule that activates nearby immune cells, the team has demonstrated a significant advancement in cancer treatment. This dual approach, which combines activating the cGAS-STING pathway with existing immunotherapy drugs known as checkpoint blockade inhibitors, showed promising results in a study involving mice.

The study, led by Natalie Artzi, a principal research scientist at MIT’s Institute for Medical Engineering and Science, utilized messenger RNA to deliver the necessary instructions to cancer cells to produce the signaling molecule, cGAMP. This technique may offer a safer alternative to administering large doses of STING activators, reducing the likelihood of side effects associated with conventional treatments.

“Our approach harnesses the tumor’s own machinery to produce immune-stimulating molecules, creating a powerful antitumor response,” Artzi stated. By increasing cGAS levels within cancer cells, the researchers enhanced the delivery efficiency of immune-stimulating signals, thereby improving the immune response while minimizing toxicity.

The cGAS-STING pathway plays a crucial role in initiating immune responses. When activated, it triggers the production of type one interferons, which stimulate immune cells to recognize and attack tumor cells. Although previous research has explored using STING agonists to artificially stimulate this pathway, clinical trials have faced challenges due to the side effects of high doses.

In their innovative approach, the researchers injected mRNA encoding cGAS, encapsulated in lipid nanoparticles, directly into tumors in a mouse model of melanoma. The results indicated that while both the mRNA treatment and the checkpoint inhibitor slowed tumor growth individually, the combination of both therapies yielded the best outcomes. In fact, tumors were completely eliminated in 30% of the mice receiving both treatments, while none of the tumors regressed in the groups that received only one type of treatment.

An analysis of the immune response revealed that the mRNA treatment stimulated the production of interferon and numerous immune signaling molecules, activating various immune cells, including macrophages and dendritic cells. These immune cells are pivotal in stimulating T cells, which are responsible for destroying cancer cells.

By utilizing a small dose of cancer-cell-produced cGAMP, the researchers aimed to circumvent one of the major obstacles associated with STING agonist therapies, which often require large doses that can lead to inflammation and damage to surrounding tissues. The localized delivery of mRNA nanoparticles allowed the cGAMP to remain concentrated at the tumor site, enhancing its effectiveness.

“The side effects of this class of molecule can be pretty severe,” Cryer noted, emphasizing the potential advantages of their method in mitigating toxicity compared to administering free molecules directly.

Looking forward, the research team plans to refine their delivery system for systemic injections rather than direct tumor injections. They also aim to test the mRNA therapy in combination with chemotherapy drugs or radiotherapy, which could enhance treatment efficacy due to increased double-stranded DNA availability for cGAMP synthesis.

This research, which appears in the Proceedings of the National Academy of Sciences, represents a significant step toward developing safer and more effective cancer immunotherapies.

For more information, readers can refer to the original publication by Artzi and colleagues titled “Restoration of cGAS in cancer cells promotes antitumor immunity via transfer of cancer cell–generated cGAMP.”