Triggering the STING Pathway Suppresses Cancer Metastasis

Most cancers would become manageable if metastasis could be eliminated. A robust way to fully suppress metastasis across all forms of cancer would not be a cure in and of itself, but it would greatly reduce mortality and allow cancers to be managed or eliminated more readily, and with less trauma for the patient. On the way to a hypothetical end to metastasis, researchers are making inroads towards approaches that may at least reduce metastasis to some degree. These approaches often, as here, involve ways to enlist the immune system to more aggressively target and destroy metastatic cells before they can build a new tumor.

Even when a primary tumor is successfully treated, cells that have broken away from the tumor often linger in the body in a dormant state that allows them to evade detection by the immune system for years at a time. Then, after the dormant cells have developed new traits to help them survive, they can wake up and start their runaway growth again. "These tumor cells are not in a supportive environment at the beginning. So they have to adapt and develop their own self-supporting niche until they're ready, eventually, to wake up and start a fast-growing metastasis. The interaction with the person's immune system is very important to this process."

Using mouse models of early-stage metastasis from lung cancer, the research team conducted a genetic screen to look at the activity of genes in the tumor cells that are important for interactions with the host's immune system. That's how they identified the STING pathway - an acronym for stimulator of interferon genes - as a suppressor of metastatic outbreaks. Importantly, the researchers found that STING expression changes across different stages of metastasis. In the dormant stage, STING activity is low - and the dormant cells excel at hiding out from immune defenders. Moving out of the dormant stage and into an awakened, proliferative stage, the metastatic cells start to have increased STING activity. This makes them more vulnerable to attack by the immune system. But cells that survive this bottleneck to generate larger clusters, called macrometastastes, again show reduced STING levels, which makes them more resistant to the immune system.

Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body's immune defenders destroy them. Indeed, when scientists artificially increased STING signaling in those aggressive metastatic cells, they attracted more immune defenders like natural killer cells and T cells, which swooped in to kill them off. And when the scientists activated STING in mice lacking key immune cells, metastasis still developed - pointing to a critical role for STING in recruiting the immune cells to attack the cancer cells.