Cancer metastasis, the spread of cancer to organs, is a major cause of cancer-related deaths. Once cancer spreads to multiple organs, conventional treatments like surgery, radiation, and chemotherapy become less effective. Scientists at Shinshu University School of Medicine have developed a synthetic mRNA that, when injected, revitalizes the immune system to recognize and attack metastasizing cancer cells. This breakthrough could lead to new therapies to improve survival rates for cancer patients.
Cancer continues to be a major global health challenge with concerning trends of rising cases. Metastasis—the spread of cancer cells from primary tumors to distant organs—poses the biggest barrier to successful treatment, accounting for a majority of cancer-related deaths. This process is intricate, involving cancer cells, immune components, and the surrounding tissue.
Cancer cells use sophisticated strategies to suppress the immune system and spread in the body. For instance, immune cells like natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), responsible for attacking tumors, are reprogrammed to create an immunosuppressive environment, making it harder for the body to fight back. Additionally, these cells often become dysfunctional or exhausted, losing their ability to effectively kill cancer cells.
The research team, led by Professor Sachie Hiratsuka and Associate Professor Takeshi Tomita from Shinshu University School of Medicine, along with Professor Yoshihito Ueno from Gifu University, developed a synthetic messenger RNA (s-mRNA) that activates immune cells to counter this suppression. The mRNA can be injected intravenously into the body, strengthening the immune response against metastasizing cancer cells.
These findings, published online in the journal Nature Communications on 25 February 2025, could pave the way for new anti-cancer therapies. "This study introduces a promising method to prevent tumor metastasis. If further developed, it could improve cancer survival rates," says Dr. Tomita.
The researchers based their s-mRNA on full-length IL1β-mRNA, which they originally identified in the lungs of mice before metastasis occurred. This mRNA activates immune cells by binding to ZC3H12D, an RNA-binding protein on NK cells. However, the natural IL1β-mRNA is unstable and degrades quickly due to RNases (enzymes that break down RNA molecules). To increase stability, the researchers designed a shorter synthetic IL1β-mRNA, retaining the essential immunostimulatory sequence that binds to the ZC3H12D receptor. They also chemically modified the mRNA to protect it from degradation by RNases, allowing it to remain intact in mouse and human serum for up to 48 hours.
When injected intravenously, the mRNA binds to NK cells and CTLs and enters the nucleus, where it triggers the production of GZMB, a key molecule for tumor-killing activity (see Figure 1). Importantly, this process does not cause a cytokine storm, which is a harmful overreaction of the immune system. To evaluate its effectiveness, the researchers administered the s-mRNA to tumor-bearing mice, mimicking metastasis from primary tumors. The mice were implanted with breast cancer (E0771) and colon cancer (MC-38) cells to create primary tumors, and cancer cells were injected into the bloodstream to stimulate metastasis. Remarkably, just three small doses of the s-mRNA each as low as 1 μg injected into the tail vein of the mouse, significantly reduced the number of metastatic cells in the lungs (see Figure 2).
Importantly, the immune cells retained their tumor-fighting capabilities for several days after mRNA administration. In mouse models simulating metastasis after surgery, where the primary tumor was surgically removed, mice that received sIL1β-mRNA treatment had significantly fewer metastatic foci (small clusters of cancer cells that represent the early stages of metastasis) 21 days after administration compared to the control group.
The mRNA also showed promise for use in human patients. When injected into weakened immune cells taken from patients with colon cancer, the s-mRNA reactivated them, enabling them to kill 70% of cancer cells. The treatment was effective even in patients undergoing anticancer drug therapy or those with multiple cancers, outperforming IL-12, a cytokine known to stimulate immune cells. Moreover, the mRNA treatment could be combined with other therapies such as anti-PD1 antibodies to further improve outcomes.
With its safety, ease of delivery, and effectiveness against metastatic cells, this treatment offers promise for cases where traditional cancer therapies often fall short. "One of the key advantages of the s-mRNA treatment is that it can be administered in multiple doses without causing unwanted inflammatory side effects," says Prof. Hiratsuka. This breakthrough could lead to new treatments that work independently or in combination with existing therapies, significantly improving the survival rates of patients with metastatic cancer.
