Scientists find the gene that drives T-cell exhaustion, revealing new strategy to improve immune responses
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Immunotherapy, which uses a patient's immune system to treat disease, has increased survival for some adults and children with cancer. However, it has had limited success against many pediatric solid tumors, in part because T cells can become functionally impaired or "exhausted." St. Jude Children's Research Hospital scientists published results in Nature showing that the gene ZMYND8 is a major regulator of CD8+ T-cell exhaustion. The results also showed that removing the gene improves antitumor and antiviral responses on its own and may have a synergistic effect with immunotherapy.
The immune system uses CD8+ T cells to attack virally infected or cancerous cells. However, when CD8+ T cells are exposed to disease-related signals for too long, such as those from solid tumors or chronic viral infections, they can become overstimulated. That overstimulation causes CD8+ T cells to be activated less effectively by a T-cell-stimulating signal called interleukin-2 (IL-2). The T cells enter an exhausted state with limited function, unable to stop the tumor or infection from progressing.
St. Jude investigators searched for the molecular link between overstimulation and exhaustion to see whether they could prevent exhaustion and increase immune control of these diseases. They found their answer in ZMYND8.
"Now we may have a way to overcome CD8+ T-cell exhaustion and improve their function," said corresponding author Hongbo Chi, Ph.D., chair of the St. Jude Department of Immunology. "When we deleted Zmynd8, we saw improved CD8+ T-cell function against tumors and chronic infections, suggesting we may have a new therapeutic target to explore to improve these therapies."
The protein ZMYND8 normally acts as a molecular brake on the expression of certain genes, such as that of the IL-2 receptor (Il2ra). The study shows that ZMYND8 can be co-opted by chronic viral infection and some cancers to turn off activation signals in CD8+ T cells. Removing the corresponding gene from CD8+ T cells improved control of chronic viral infection and melanoma in mouse models compared with controls. Still, the researchers found they could improve these results even more.
"What we're really excited about is how the combination with immunotherapy enhanced treatment efficacy," Chi said.
Because loss of ZMYND8 improved immune function, the scientists tested whether deleting the gene could work with established immunotherapy approaches. They combined Zmynd8 deletion in CD8+ T cells with immune checkpoint blockade (drugs that block cancer's ability to hide from the immune system) or IL-2. In both cases, they observed an increase in functional cells, a decrease in exhausted cells and an even greater improvement in survival among mice receiving the combination treatments.
The findings suggest that targeting ZMYND8 may be a strategy to overcome CD8+ T-cell exhaustion and improve immunotherapy.
Finding the source of T-cell exhaustion
To find out what regulates CD8+ T-cell exhaustion, the researchers used single-cell CRISPR screening to examine the effects of removing genes involved in gene expression. "We found that ZMYND8 is a 'master' regulator of CD8+ T-cell exhaustion," said co-first author Yan Wang, Ph.D., of the St. Jude Department of Immunology. "Its deletion enhanced effector cell formation, leading to the improved antitumor and antiviral effects we observed."
After identifying this master regulator, the team sought to understand how it controlled CD8+ T-cell fate. The researchers found that ZMYND8 binds to and suppresses the activity of p300, which controls the transcriptional activation of the IL-2 receptor gene. This finding reveals the molecular link between overstimulation and CD8+ T-cell exhaustion.
"ZMYND8 can transform the chronic antigen stimulation signal that occurs in chronic viral infections and cancer into suppression of IL-2 receptor signaling, leading to an exhausted cell state," said co-first author Hao Shi, Ph.D., of the St. Jude Department of Immunology.
With a clear map of how ZMYND8 leads to CD8+ T-cell exhaustion, researchers can explore how to enhance immunotherapy efficacy even more. "We have a new approach that could synergize with immunotherapy," Chi said. "One day, a combination treatment approach could improve survival for patients with solid tumors."
Publication details
Yan Wang et al, Targeting ZMYND8 unleashes IL-2 signalling to override T cell exhaustion, Nature (2026). DOI: 10.1038/s41586-026-11059-5
Journal information: Nature
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OncologyAllergy and immunology Provided by St. Jude Children's Research Hospital Who's behind this story?
Lisa Lock
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