How the Brain Defends Itself From Cancer: Scientists Record the First Contact Between Microglia and Metastatic Cells

Scientists have, for the first time, observed in real time how the brain’s immune cells — microglia — encounter cancer cells attempting to enter the brain and form metastases.

The study reporting this discovery was published in Cancer Research.

Metastasis is the leading cause of cancer-related death, and brain metastases are particularly dangerous: they develop in 10–30% of patients with advanced lung cancer, breast cancer, and melanoma. Modern treatments can target tumors that have already formed, but they almost never affect the earliest “seed” cells that first enter the brain — cells that can still be destroyed by the immune system.

Microglia are the brain’s guardian cells. They can quickly recognize and digest harmful cells, including tumor cells. However, researchers had long been unable to understand why microglia sometimes fail to eliminate cancer cells. The main obstacle was the lack of technology capable of capturing this process in the living brain.

A team led by Takahiro Tsuji at Nagoya University School of Medicine has now recorded the moment of contact between microglia and cancer cells using two-photon microscopy. The researchers examined cells that migrate to the brain from the lungs — a major source of brain metastases. Importantly, the “window of opportunity” during which microglia can destroy these cells lasts only about 12 days. By the time symptoms appear or MRI scans reveal abnormalities, metastases are already formed.

The researchers found that some microglial cells do attack and digest cancer cells — but others, conversely, help them survive and grow. To understand this difference, the scientists used an “opto-omics” method that allowed them to isolate only those microglial cells that physically interact with tumor cells and analyze them.

The key discovery: cancer cells use two proteins — CD24 and CD47 — to send microglia a “don’t eat me” signal. When the researchers genetically removed these proteins, microglia efficiently destroyed the “seed” cells, and the number of metastases dropped sharply. Moreover, CD24 and CD47 were found in half of patients with brain metastases from lung cancer, underscoring the clinical significance of the finding.

The scientists propose a strategy for early intervention: blocking CD24 and CD47 with antibodies or other drugs to help microglia eliminate metastatic cells before a tumor forms. In parallel, the team is developing biomarkers to identify patients for whom such therapy would be most effective, and plans to apply their technology to study metastases in other organs as well.