Almost one-third of cancer patients develop brain metastases. This stage has traditionally been considered the final, incurable stage of aggressive cancer, to the point that patients who reached it were excluded from clinical trials due to their poor prognosis. In recent years, groups such as the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO) have opened new avenues for treating brain metastases.
The CNIO team, led by Manuel Valiente, has broadened the scope of its research to focus on what happens in the environment surrounding brain metastases. Over the last decade, findings from this laboratory have led to the conclusion that metastasis occurs when tumor cells create an environment suited to their needs, and to do so, “they must alter the brain themselves,” explains Valiente.
When tumor cells reach the brain, most are eliminated because they lack the means to grow in this organ; only a few possess the necessary abilities to reshape the brain and adapt it to their needs. Tumor cells begin to alter the tissue, activate molecular pathways that should be inactive, and, ultimately, create an environment favorable only to themselves. This allows them to spread uncontrollably and reproduce the tumor.
Valiente’s group has already uncovered how several of these molecular changes occur, and is testing drugs to block them and thus prevent this abnormal remodeling in the brain.
They have now discovered another mechanism that could be valuable in treating brain metastases from various types of tumors, as well as other non-tumor conditions affecting the brain. Furthermore, this mechanism can be targeted by a drug that penetrates the brain effectively and is well tolerated, as it is approved for the treatment of asthma in other countries.
The finding is published today in the journal Cancer Research , with Laura Álvaro-Espinosa as first author. Valiente aims to initiate a clinical trial in the medium term.
Defensive cells hijacked by cancer
The new target is a protein called MIF, which, produced by tumor cells in the brain, acts like a key that is never used in this organ. The new study shows that MIF binds to a molecular structure—called CD74—found on the surface of a type of cell responsible for alerting the immune system, namely macrophages and microglia.
In normal conditions these CD74-expressing cells would fight metastasis, as they are part of the immune system; with the MIF molecular key, however, metastatic cells use CD74 to make them work to the advantage of the cancer. MIF reprograms this cell type to drive tumor growth.
In their search for a way to prevent MIF from transforming CD74-expressing macrophages, the CNIO team discovered the drug ibudilast, which is known to block the binding of MIF to CD74. Their results show that ibudilast slows metastasis in both animal models and fresh patient samples derived from different primary tumors.
“We demonstrate that microglia and CD74+ macrophages are reprogrammed, shifting from a potentially antitumor nature to a pro-metastatic one in the brain,” the researchers say.
Also in Alzheimer’s and Multiple Sclerosis
The authors also highlight another observation from their study: the functional shift of CD74+ cells due to MIF action is also detected in neurodegenerative and neuroinflammatory diseases, such as Alzheimer’s and multiple sclerosis. The new finding could also be relevant for these diseases, as has recently been observed in primary brain tumors, such as glioblastoma.
For Valiente, “MIF-mediated reprogramming may be a common vulnerability in various brain diseases, a shared mechanism that can be therapeutically targeted.”
The findings of the CNIO Brain Metastasis Group suggest that changes occurring in this organ may provide clues not only about metastasis but also about other degenerative and neuroinflammatory diseases.
The Value of the World’s First Bank of Fresh Brain Metastasis Samples
This finding is further proof of the value of two major achievements by the CNIO group: the creation of the world’s first bank of fresh brain metastasis samples, RENACER ; and the drug testing platform that these samples have enabled to be developed, METPlatform .
Both resources—the repository and the platform—are innovative research tools celebrated by the international neuro-oncology community, and have already led to several clinical trials currently underway.
An urgent clinical need
Valiente notes that finding specific therapies for brain metastases is urgent, as this represents “an unmet clinical need.” Up to 30% of cancer patients develop brain metastases, particularly from breast, lung, skin, and colorectal tumors. However, there is currently no specific treatment for these patients beyond surgery and radiation therapy.
Reference:
MIF-Induced CD74+ Microglia 1 and Macrophages Promote Progression of Brain Metastasis and are Clinically Relevant Across Central Nervous System Disorders
https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-25-4018
About the Spanish National Cancer Research Centre (CNIO)
The Spanish National Cancer Research Centre (CNIO) is a public research centre under the Ministry of Science, Innovation, and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It brings together some 500 scientists, plus support staff, who work to improve cancer prevention, diagnosis, and treatment.
Captions and credit:
Manuel Valiente, head of the Brain Metastasis group at the Spanish National Cancer Research Centre (CNIO). /Laura M. Lombardía. CNIO
Laura Álvaro-Espinosa, researcher in the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO). / Christian Esposito. MadMoviex.
Scientific image:
CD74⁺ microglia/macrophages surrounding and infiltrating experimental brain metastasis. Representative immunofluorescence image of a brain metastasis derived from the human lung adenocarcinoma cell line H2030-BrM following intracardiac injection in mice. Tumor cells are labeled with GFP (green), microglia/macrophages with Iba1 (blue), and CD74 expression is shown in red.
Cancer Research
Experimental study
Human tissue samples
24-Mar-2026
M.V. has received research funding from AstraZeneca. The rest of the authors 82 declare no conflict of interest.