Brain metastases are one of the most severe complications of melanoma, the most aggressive type of skin cancer. Researchers at the Institute for Neurosciences, a joint center of the Spanish National Research Council and the Miguel Hernández University in Elche, have identified a strategy to slow their progression, which could improve the response to current treatments. The study, published in Cancer Cell, demonstrates that microglia, a type of resident immune cell in the brain, can be manipulated to reduce brain metastases growth and enhance immunotherapy responses in preclinical mouse models. In sum, researchers discovered that microglia can be reprogrammed from a tumor-promoting state to one that strengthens antitumor responses. Using mouse models of brain metastases and advanced sequencing techniques, the researchers analyzed the role of microglia in this context.
And demonstrated that when they 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 (NK) cells, which effectively attack tumor cells.The researchers also analyzed patient samples, confirming that this strategy could have future clinical applications. Additionally, the team observed that blocking this signaling pathway also enhances the response to immunotherapy in preclinical mouse models. The study’s findings indicate that manipulating microglia could be used in combination with existing immunotherapies to boost their effectiveness in patients with brain metastases.This research represents a significant breakthrough in understanding the interactions between the brain’s immune system and metastases in this organ, opening new avenues to improve the prognosis of patients with advanced cancer.
These findings could lead to innovative therapeutic strategies for melanoma patients and other cancers that metastasize to the brain, such as breast or lung cancer. Particularly, combinatorial treatments based on immune checkpoint inhibition (ICI) significantly increase the clinical benefit for a proportion of patients. However, there are still many patients not benefiting from ICI, including those with symptomatic melanoma brain metastases or receiving steroids. Here, the research team showed that Rela/NF-κB targeting also promotes intracranial responses to anti-PD-L1 and to dual anti-PD-1/anti-CTLA-4 therapy in a relevant NRas-driven melanoma brain metastases preclinical model. The selective targeting of NF-kB transcription factor has always been tempting to hit the immune system and inflammation; yet, except for steroids, no official drugs is clinically available to directly suppress this cellular regulator.
Dr. Sánchez-Laorden, lead author of this investigation, commented: “Immune checkpoint inhibitors have revolutionized melanoma treatment, but not all patients respond well to these therapies. Our study suggests that combining them with Rela/NF-kB inhibitors could improve their effectiveness in treating brain metastases. These results allow us to explore new therapeutic combinations that could significantly improve patient survival. This is just the beginning. 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”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Rodriguez-Baena FJ et al. Cancer Cell. 2025 Feb 4; in press.
Ma W, Oliveira-Nunez MC et al. Nat. Commun. 2023; 14:2632.
Dumas AA, Pomella N al. EMBO J. 2020; 39:e103790.
