In a preclinical study published in Nature Communications, a team led by Juliana (Hofstatter Azambuja) Yerneni, Ph.D., a researcher in the Department of Laboratory Medicine and Pathology at Mayo Clinic, identified a protein called MALT1 as a critical molecular switch governing this immunological betrayal. MALT1 is an enzyme—a protease—best known for its role in immune cell signaling, where it cleaves other proteins to transmit activation signals in lymphocytes. But the Mayo Clinic team discovered that in the environment of glioblastoma, MALT1’s enzymatic activity plays a far more sinister role: it helps maintain tumor-associated macrophages and other myeloid immune cells in a state that suppresses antitumor immunity rather than promoting it.

Tumor-associated macrophages are among the most abundant immune cells in glioblastoma, and they represent one of the central paradoxes of brain cancer immunology. In theory, macrophages are professional destroyers of abnormal cells, capable of engulfing debris, presenting antigens, and summoning other arms of the immune system to a site of danger. In glioblastoma, however, the tumor co-opts these cells through a barrage of molecular signals, reprogramming them into what researchers often describe as an immunosuppressive state. Instead of rallying an immune assault, they release factors that dampen T cell activity, promote tumor blood vessel formation, and physically construct a protective niche around the cancer. This manipulated microenvironment is a major reason why glioblastoma has proven so resistant to the wave of immunotherapies that have transformed treatment for many other cancers.

The Mayo Clinic team hypothesized that interrupting the signaling pathways that sustain this reprogramming could destabilize the tumor’s protective shield. Their attention settled on MALT1, a protein whose protease activity sits at a critical junction in immune signaling cascades. Using pharmacological inhibitors designed to block MALT1’s enzymatic function, the researchers found that suppressing the protein fundamentally altered the behavior of the immune cells surrounding glioblastoma tumors. Rather than maintaining their tumor-protective, immunosuppressive identity, the macrophages and related myeloid cells shifted toward a state that actively promoted antitumor immune responses. In effect, the guards the tumor had bribed were turned back into soldiers.

The consequences of this reprogramming were striking in preclinical models. When the researchers treated animals bearing glioblastoma with MALT1 inhibitors, tumor growth slowed measurably. The treatment did not merely affect the immune landscape; it translated into tangible control of tumor progression. Encouraged by these results, the team next explored what would happen when MALT1 inhibition was paired with temozolomide, the alkylating chemotherapy that has formed the backbone of glioblastoma treatment since the early 2000s. The logic was compelling: if an immunosuppressive microenvironment blunts the effectiveness of conventional therapy, then dismantling that environment should allow the chemotherapy to do its job more thoroughly.

The combination outperformed expectations. In preclinical models, adding MALT1 inhibition to temozolomide enhanced the chemotherapy’s effectiveness, and in one model, median survival increased substantially compared with treatment using temozolomide alone. For a disease in which median survival with standard care remains measured in months, any substantial extension in a preclinical setting represents a meaningful signal—one that justifies pushing the strategy toward further development.

“Glioblastoma is extraordinarily difficult to treat, in part because the tumor is able to manipulate the immune cells around it and create an environment that protects the cancer,” Yerneni explained in the announcement of the findings. “Our findings point to a potential approach to disrupting that protection and, importantly, to making an existing treatment more effective.”

The clinical stakes could hardly be higher. Glioblastoma accounts for roughly half of all malignant brain tumors in adults and, according to the Mayo Clinic team, represents about 5% of malignant brain tumors in children. Despite decades of effort—aggressive surgery, radiation, and temozolomide-based chemotherapy—the disease remains incurable and almost invariably recurs. Patients diagnosed with glioblastoma face one of the bleakest prognoses in oncology, and the treatment landscape has seen remarkably little meaningful change in nearly two decades. The blood-brain barrier excludes many drugs, the tumor infiltrates healthy brain tissue in finger-like projections that defeat even the most skilled surgeons, and its immunosuppressive microenvironment neutralizes many of the immune-based approaches that have succeeded elsewhere in the body.

Against that grim backdrop, the appeal of the MALT1 strategy lies partly in its simplicity of concept. Rather than attempting to introduce an entirely new therapeutic modality into the brain—a formidable logistics problem given the barriers protecting the central nervous system—the approach seeks to repurpose and amplify the power of a drug that already reaches patients today. Temozolomide is an oral chemotherapy that damages tumor DNA, but its efficacy is limited both by DNA repair mechanisms within tumor cells and by the hostile, immune-suppressed environment that glioblastoma cultivates. By reprogramming the macrophage population around the tumor, MALT1 inhibition appears to address the second of those limitations, creating conditions under which temozolomide’s cytotoxic effects can produce greater clinical benefit.

The work also contributes to a broader and increasingly influential theme in cancer research: the recognition that the tumor microenvironment is not passive scenery but an active participant in disease progression. Over the past two decades, immunotherapy—checkpoint inhibitors, CAR T cells, cancer vaccines—has demonstrated that mobilizing the immune system can produce durable remissions in melanoma, lung cancer, blood cancers, and others. Glioblastoma has stubbornly resisted these advances, in large part because of the myeloid cell-dominated, profoundly immunosuppressive nature of its microenvironment. Strategies that specifically target the mechanisms by which tumors corrupt myeloid cells, rather than merely attempting to stimulate T cells directly, may therefore be better suited to the unique immunology of brain cancer. MALT1 inhibition belongs to this emerging class of approaches.

The research program behind the study is led by senior authors Linda McAllister, M.D., Ph.D., a pediatric oncologist and enterprise deputy director for pediatric cancer programs at the Mayo Clinic Comprehensive Cancer Center, and Peter Lucas, M.D., Ph.D., vice chair for research in the Department of Laboratory Medicine and Pathology. Their laboratory’s overarching mission, as McAllister described it, is to understand how glioblastoma communicates with surrounding immune cells to dampen antitumor immunity, and to translate those discoveries into treatments that strengthen the immune response and improve outcomes for patients with this devastating disease. The fact that the work has relevance for pediatric as well as adult disease adds an additional dimension of urgency, given how limited treatment options are for children with malignant brain tumors.

Importantly, the researchers and their institution are careful to frame the findings as preclinical. Mouse models of glioblastoma, while invaluable, have a notoriously imperfect record at predicting clinical success in humans, and many promising immunotherapies have faltered in translation to brain tumor patients. Several questions remain open. Which molecular subtypes of glioblastoma are most dependent on MALT1-driven myeloid programming, and therefore most likely to respond to the therapy? How would a MALT1 inhibitor behave in the human brain, and what safety considerations arise from targeting a protein that also plays important roles in normal immune cell function? Could long-term suppression of MALT1 compromise the immune system’s ability to fight infection? Answering these questions will require extensive additional research before the strategy can be evaluated in clinical trials.

Even so, the study offers something that glioblastoma research has rarely produced: a mechanism-based way to make an existing therapy meaningfully more effective while simultaneously converting the tumor’s own defenses into vulnerabilities. The idea that flipping the state of a single population of immune cells could slow tumor growth and extend survival—and that doing so could unlock greater benefit from a two-decade-old chemotherapy—captures the kind of elegant biology-meets-therapeutics reasoning that the field has long hoped for. As the Mayo Clinic team continues its work to identify which patients’ tumors are most likely to respond, the findings stand as a reminder that the immune cells surrounding a tumor, once seen as part of the problem, can be reimagined as part of the cure.

For patients and families confronting one of medicine’s most feared diagnoses, such reimagining is not merely an academic exercise. It represents the beginning of a potential path toward treatments that do not simply attack the tumor more aggressively, but intelligently dismantle the shield it has built—and then strike.

News Publication Date: 9-Sep-2026

Web References: https://www.nature.com/articles/s41467-026-76572-7

References: Yerneni, J. H. A., et al. (2026). MALT1 protease inhibition restrains glioblastoma progression by reversing tumor-associated macrophage-dependent immunosuppression in mice. Nature Communications. https://www.nature.com/articles/s41467-026-76572-7

Glioblastoma is characterized by its remarkable heterogeneity, aggressive invasion into surrounding brain tissue, and an uncanny ability to evade existing therapies, leading to dismal patient prognoses. Central to this malignancy is a subpopulation of cancer stem-like cells that drive tumor recurrence and therapeutic resistance. SOX9, a transcription factor well-known for its roles in development and stem cell biology, has emerged as a key player in maintaining this stem-like state. However, the post-translational dynamics that govern SOX9 stability within glioblastoma cells were poorly understood until now.

The study elucidates how USP18, a ubiquitin-specific protease, functions as a deubiquitinase for SOX9, effectively rescuing it from proteasomal degradation. Ubiquitination is a cellular process that tags proteins for destruction; in contrast, deubiquitination removes these tags, rescuing proteins from being broken down. By stabilizing SOX9, USP18 ensures the persistence of its oncogenic functions, such as promoting self-renewal, proliferative capacity, and survival of glioblastoma stem-like cells. This molecular axis thus represents a critical node in the maintenance of glioblastoma’s aggressive phenotype.

The researchers employed a combination of biochemical analyses, genetic manipulation, and in vitro and in vivo models to dissect the role of USP18 in glioblastoma. They demonstrated that knocking down USP18 leads to increased ubiquitination and subsequent degradation of SOX9, thereby impairing the stemness and proliferation of glioblastoma cells. Conversely, USP18 overexpression stabilized SOX9 and enhanced malignant properties, confirming the enzyme’s oncogenic influence. These manipulations directly impacted tumor growth rates and invasion capabilities in animal models, underscoring the clinical relevance of the findings.

Mechanistically, the deubiquitination activity of USP18 targets specific lysine residues on SOX9, preventing proteasome-mediated destruction. This direct interaction was confirmed through co-immunoprecipitation and ubiquitination assays, pinpointing USP18 as an indispensable regulator of SOX9 protein homeostasis. The stabilization of SOX9 consequently sustains the gene expression programs vital for glioblastoma stemness, including the regulation of pathways involved in cell cycle progression, survival, and DNA damage response.

Beyond the molecular interaction, the study sheds light on the broader oncogenic landscape of glioblastoma. The USP18-SOX9 axis represents a critical link connecting post-translational modification machinery to transcriptional control mechanisms sustaining tumor aggressiveness. Given the notorious difficulty in targeting transcription factors like SOX9 directly, USP18 emerges as an attractive druggable target. Inhibiting USP18’s enzymatic activity could destabilize SOX9, thereby attenuating the tumor’s stem cell-like properties and sensitizing glioblastoma cells to chemotherapy and radiotherapy.

Importantly, USP18 has been previously implicated in immune regulation and interferon signaling, indicating potential pleiotropic effects of targeting this protease. This dual functionality necessitates a nuanced therapeutic approach, possibly involving USP18 inhibitors tailored to selectively disrupt its interaction with SOX9 without compromising essential immune functions. The study’s insights into the specificity of USP18’s substrate interactions provide a valuable foundation for designing such targeted inhibitors.

In addition to therapeutic implications, this discovery advances the fundamental biology of glioblastoma by highlighting how protein stability regulation intricately controls cancer stem cell phenotypes. The ability of USP18 to modulate SOX9 protein levels post-translationally exemplifies the complex regulatory networks cancer cells leverage to maintain their malignant features. This underscores an emerging theme in oncology where deubiquitinases play central roles in sustaining oncogenic signaling pathways.

Further exploration of the USP18-SOX9 axis revealed that this interaction is dynamically regulated in response to environmental stressors and therapeutic pressures. For instance, hypoxic conditions within the tumor microenvironment and exposure to genotoxic agents appear to enhance USP18 expression, thereby reinforcing SOX9 stabilization and contributing to therapy resistance. Understanding these adaptive responses could inform the timing and combination of USP18-targeted therapies to maximize clinical efficacy.

Moreover, the spatial and temporal expression patterns of USP18 and SOX9 were characterized in glioblastoma patient samples, correlating high levels of both proteins with poorer clinical outcomes. This clinical correlation strengthens the translational relevance and positions USP18-SOX9 as a prognostic biomarker axis. Consequently, assessing USP18 and SOX9 expression could guide patient stratification and personalized treatment regimens designed to inhibit this malignant circuitry.

This landmark study expands the therapeutic horizon for glioblastoma by highlighting a novel vulnerability in the cancer’s molecular armor. Targeting the USP18-mediated stabilization of SOX9 presents a compelling strategy to dismantle the self-renewing tumor cell compartment that drives recurrence and resistance. As glioblastoma continues to defy conventional therapies, such innovative molecular insights offer a beacon of hope for developing more effective treatments and improving patient survival.

Future research directions will focus on developing small-molecule inhibitors or biologics that disrupt USP18’s catalytic function or its binding interface with SOX9. Additionally, integrating USP18 targeting with existing modalities, such as immune checkpoint blockade and radiotherapy, may produce synergistic effects. Combining these approaches could help overcome the multifaceted defense mechanisms glioblastoma employs, ushering in a new era of precision oncology tailored to the disease’s molecular underpinnings.

In conclusion, the study’s identification of USP18 as a master regulator of SOX9 stability and glioblastoma stemness represents a profound leap forward in understanding the disease’s biology. It exemplifies how deciphering post-translational modifications can reveal hidden drivers of tumor aggressiveness and resistance. With USP18’s enzymatic activity acting as a linchpin in maintaining the malignant phenotype, targeted interventions disrupting this axis hold transformative potential for combating glioblastoma’s devastating impact.

Subject of Research: Regulation of glioblastoma stemness and malignancy via USP18-mediated deubiquitination and stabilization of SOX9.

Article Title: USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma.

Article References:
Liu, Z., Yu, K., Chen, K. et al. USP18 deubiquitinates and stabilizes SOX9 to promote the stemness and malignant progression of glioblastoma. Cell Death Discov. 11, 237 (2025). https://doi.org/10.1038/s41420-025-02522-9

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41420-025-02522-9