Brain Cancer: Blocking a Protein May Hold the Key to a Cure

Researchers have discovered that blocking the protein ZNF638 can help the immune system attack glioblastoma, an aggressive type of brain cancer. This protein normally silences parts of the DNA that would activate defenses against the tumor. By inhibiting it, the cancer begins to resemble a viral infection, activating the immune system. In tests, this improved the response to immunotherapy and increased survival in patients. These findings could lead to new treatments for glioblastoma and other types of cancer.

Glioblastoma (GBM) is the most common type of malignant brain tumor in adults and, unfortunately, has a very low survival rate that has barely changed in the last 20 years.

Conventional treatments, such as surgery, chemotherapy and radiation therapy, are not completely effective, so scientists are looking for new strategies.

One of these is Immune Checkpoint Inhibition (ICI), a form of immunotherapy that has already shown good results in other types of cancer. However, in cases of glioblastoma, this approach has failed for several reasons: the immune system does not recognize the tumor cells well, there are few lymphocytes (defense cells) infiltrated in the tumor, and the tumor microenvironment itself makes it difficult for immunotherapeutic drugs to act.

To get around this problem, scientists have begun to explore a strategy called “viral mimicry.” This concept is based on the fact that certain parts of human DNA, known as retrotransposons, resemble ancient viruses that have been incorporated into our genome.

Normally, these sequences are “deactivated” through epigenetic modifications (chemical marks that control the activation of genes). However, in some situations, such as glioblastoma, these sequences can be reactivated, triggering an immune response similar to that which occurs when the body detects a real virus.

This activation can help the immune system to better recognize tumor cells and enhance the effect of immunotherapy.

One way to regulate these retrotransposons is through an epigenetic mark called H3K9me3, which prevents these sequences from being activated. This process is mediated by the HUSH complex, a set of proteins that acts as a “blocker” for these viral sequences within the DNA.

One of the regulators of this process is the protein ZNF638. This protein helps to "silence" parts of the DNA that could activate an immune response against the tumor.

By blocking ZNF638, scientists were able to reactivate these parts of the DNA, triggering an effect called "viral mimicry", which makes the tumor cells appear to be infected by a virus. This attracts the immune system to attack the tumor.

The experiments showed that blocking ZNF638 in glioblastoma models led to an increase in the activation of immune pathways, greater expression of PD-L1 (a protein important for the immune response) and greater infiltration of immune cells into the tumor.

In addition, tests in mice showed that this strategy made the tumors more sensitive to immunotherapy treatment, leading to better results.

This study examined the relationship between the expression of a specific type of genetic material (dsRNA) and the immune response in patients with an aggressive type of brain cancer, recurrent glioblastoma (GBM). In the first case analyzed (A), a 60-year-old patient with GBM was treated with an immunotherapy called a PD-1 inhibitor (anti-PD-1). Before treatment, the tumor had a low presence of CD8+ defense cells (cyan) and little expression of the PD-L1 protein (orange), which influences the immune response. Five months after surgery and immunotherapy, the MRI showed an increase in the affected area, but this did not mean that the tumor was actually growing. Instead, this effect may have been an “immune pseudoprogression,” which occurs when there is infiltration of defense cells and death of tumor cells, giving the false impression of tumor growth. Further analysis revealed that the affected area had increased expression of dsRNA (green), accompanied by an increase in CD8+ cells (cyan) and PD-L1 (orange), suggesting that the immune system was responding better to the tumor. In the second finding (B), the researchers compared patients with recurrent glioblastoma and melanoma who responded well to immunotherapy with those who did not. They observed that patients who had a good response had significantly lower levels of the protein ZNF638. Finally, in the third finding (C), they showed that patients with recurrent glioblastoma who had low levels of ZNF638 had longer survival when receiving immunotherapy (anti-PD-1 or anti-PD-L1). This suggests that ZNF638 may be hindering the immune response against the tumor and that reducing it may be a promising way to improve the effectiveness of treatments.

When scientists analyzed samples from patients with recurrent glioblastoma, they found that those with lower levels of ZNF638 had a better response to immunotherapy and longer survival. This suggests that this protein may be a promising target for improving the treatment of glioblastoma and enhancing the effect of immunotherapy.

In summary, this research suggests that inhibiting ZNF638 may be a novel approach to making the immune system more effective in fighting glioblastoma, offering new hope for patients who currently have few effective treatment options.

READ MORE:

Activating Antiviral Immune Responses Potentiates Immune Checkpoint Inhibition in Glioblastoma Models

Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan,  Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, and Ashish H. Shah

Journal of Clinical Investigation.  2025; 135(6) : e183745

DOI: 10.1172/JCI183745

Abstract: 

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.