SEPTEMBER 5, 2025, NEW YORK – The most common and aggressive type of adult brain cancer, glioblastoma multiforme (GBM) is notoriously resistant to treatment, with a median survival of just 14 months following diagnosis. Its resistance stems from the dizzying genetic variability and plasticity of glioblastoma cells—which means there’s some subpopulation of cells in every tumor impervious to any drug deployed to kill them—and from the profoundly immunosuppressive microenvironment GBM cultivates, which thwarts immunotherapies.
Now researchers led by Ludwig Lausanne’s Johanna Joyce and former postdoc Ángel Álvarez-Prado have discovered a drug target in glioblastoma cells that could potentially undermine both these sources of resistance. The researchers show in the current issue of Cell Reports that loss of a protein named ADAR1—a sort of off-switch for the anti-viral alarm system innate to mammalian cells—stalls the proliferation of distinct types of GMB cells while simultaneously reprogramming the tumor microenvironment (TME) into an anti-tumoral state.
“This study provides proof-of-concept for an entirely new strategy for GBM therapy—flipping the switch on the body’s innate virus-fighting machinery and turning it against the tumor,” said Joyce. “Using both mouse models of GBM and human brain cancer cells, we showed that disabling ADAR1, a silencer of that alarm, hampers cancer cell proliferation in human samples of GBM tumors. It also slows tumor growth and extends survival in multiple mouse models of this aggressive cancer.”
One of the mechanisms by which mammalian cells sense viral infection is through the internal detection, by innate protein sensors, of double-stranded (ds) RNA molecules that appear to be foreign in origin. The detection of such dsRNA, which can encode viral genomes, triggers an alarm: the production and secretion of type I interferons, factors that can stimulate a cascading immune response.
In healthy cells, ADAR1 helps prevent false alarms of viral infection, as these can cause autoimmune disease if they’re continually triggered erroneously. It does so by chemically modifying dsRNAs that are made by the cells themselves so that they’re recognized as “self” molecules by the cell’s internal sensors.
Recent studies have found, however, that certain types of cancer cells that continuously express interferon-stimulated genes (ISGs) are highly vulnerable to ADAR1 loss. Others have shown that deleting the ADAR1 gene in melanoma tumors can improve responses to immunotherapy in mouse models.
Álvarez-Prado, Joyce and their colleagues examined whether GBM cells also express ISGs to see if this potential vulnerability might be exploited for brain cancer therapy. They showed that GBMs not only express ISGs in many cases but that ADAR1 deletion had the additional effect of arresting cancer cell proliferation. This was seen in multiple, genetically distinct mouse models as well as cultures derived from patient tumors.
Investigating the mechanism of the effect, the researchers discovered that ADAR1-loss induces intracellular signaling that suspends protein manufacturing in GBM cells, arresting their proliferation. Notably, such effects were not seen in neural cell cultures.
The researchers showed that disabling ADAR1 amplified ISG-stimulated inflammatory responses, which had the effect of reprogramming the tumor microenvironment of multiple, genetically distinct GBM tumors. Its loss, they found, boosted the numbers of immune cells in the TME that kill cancer cells—such as CD8+ T cells, pro-inflammatory macrophages and natural killer cells—and depleted immune cells that suppress anti-tumor immune responses.
“If translated to human use, our strategy could improve on current therapeutic approaches in three ways,” said Álvarez-Prado. “First, it works across different types of glioblastoma, regardless of their genetic differences, which has proved to be a major roadblock for current therapies. Second, it exploits a vulnerability unique to cancer cells, sparing healthy cells and so offering the potential for safer treatment. And third, it delivers a one-two punch against the tumor: stopping tumor growth from the inside, while simultaneously mobilizing the immune system to attack the tumor from the outside.”
Future research in the Álvarez-Prado lab will focus on developing an ADAR1 inhibitor that can penetrate the brain and examining its effects in preclinical studies that more closely recapitulate human GBM tumors.
This study was supported by the Ludwig Institute for Cancer Research, Swiss Cancer Research, the University of Lausanne, the European Commission, the European Molecular Biology Organization, The Brain Tumor Charity (UK).
In addition to her post as a Member of the Ludwig Institute for Cancer Research, Lausanne Branch, Johanna Joyce is also a professor at the University of Lausanne.
A former postdoc in the Joyce lab, Ángel Álvarez-Prado is today a group leader at the Luxembourg Institute of Health.