Scientists Hack Brain’s Immune Cells to Fight Deadly Melanoma

In a discovery that could transform treatment for one of melanoma’s deadliest complications, scientists have found a way to reprogram the brain’s immune cells to fight cancer. The study, published today in Cancer Cell, reveals how manipulating these cells could enhance the effectiveness of existing cancer treatments and potentially extend survival for patients with brain metastases.

Researchers at the Institute for Neurosciences in Spain identified a mechanism to convert microglia – the brain’s resident immune cells – from unwitting accomplices in cancer growth to potent tumor fighters. This transformation occurs by blocking a specific molecular pathway known as Rela/NF-κB.

From Friend to Foe

Using advanced single-cell analysis and mouse models, the team discovered that microglia undergo a complex identity shift during melanoma progression. Initially protective against tumor formation, these immune cells eventually switch allegiance and begin supporting cancer growth.

“We have identified a key signaling pathway, Rela/NF-kB, that, when blocked, reverses the protumoral function of microglia and activates an immune response against tumors,” explains Berta Sánchez-Laorden, the study’s lead researcher.

Boosting Immune Response

The study shows that targeting this pathway does more than just neutralize harmful microglia – it actively recruits other immune cells to fight the cancer. “When we block Rela/NF-kB signaling in microglia, these cells begin to send signals to other immune cells, such as cytotoxic T lymphocytes and natural killer cells, which effectively attack tumor cells,” says F. Javier Rodríguez Baena, the study’s first author.

This finding is particularly significant because brain metastases typically have lower immune cell infiltration compared to tumors elsewhere in the body, making them especially difficult to treat with immunotherapy.

Enhancing Current Treatments

The research demonstrates that this approach could improve the effectiveness of existing immunotherapies. “Immune checkpoint inhibitors have revolutionized melanoma treatment, but not all patients respond well to these therapies,” notes Sánchez-Laorden. “Our study suggests that combining them with Rela/NF-kB inhibitors could improve their effectiveness in treating brain metastases.”

The team validated their findings using patient samples, suggesting the strategy could have immediate clinical relevance. This is particularly important given that melanoma has one of the highest risks of spreading to the brain among all cancers.

Looking Ahead

“This is just the beginning,” says Rodríguez-Baena. “Our next goal is to further explore how this knowledge can be translated into clinical treatments and evaluate the potential of Rela/NF-kB inhibitors already approved for other indications.”

The research represents a significant shift in understanding how brain metastases interact with their environment and suggests new therapeutic strategies not just for melanoma, but potentially for other cancers that spread to the brain, such as breast and lung cancer.