Researchers at the Salk Institute for Biological Studies, UNC Lineberger Comprehensive Cancer Center, and University of California, San Diego have identified a new genetic mechanism that influences how key immune cells decide their fate. These cells, known as CD8 “killer” T cells, either develop into durable defense cells that provide lasting protection or fall into a debilitating state known as fatigue. The study found that switching off just two genes could restore the tumor-attacking ability of exhausted T cells.
This study natureprovides a framework that may allow scientists to intentionally program T cells to maintain both long-term immune memory and potent anti-cancer activity. This discovery could have significant implications not only for the treatment of infectious diseases but also for cancer immunotherapy.
CD8 killer T cells are essential to the immune system because they find and destroy virus-infected cells and cancer cells. However, when the immune system faces a prolonged infection or tumor, these cells can gradually lose their effectiveness. Over time, they can enter a dysfunctional state called T-cell depletion, reducing their ability to eliminate threats.
Building a genetic atlas of T cell status
Protective T cells and depleted T cells appear nearly identical and are difficult to distinguish using traditional methods. To address this challenge, researchers investigated whether these different conditions could be separated based on genetic activity.
A major breakthrough came from building a detailed genetic atlas that maps the different states of CD8 T cells. This atlas shows how these immune cells vary along a spectrum from highly protective to severely protective states.
“Our long-term goal is to increase the effectiveness of immunotherapy by creating a clear ‘recipe’ for engineering T cells,” says co-author Dr. Susan Kaech, a professor at the Salk Institute at the time of the study. “To do this, we first needed to identify which molecular components are specifically active in some T-cell states and not in others. By building a comprehensive atlas of CD8 T-cell states, we were able to pinpoint key elements that define protective and dysfunctional programs, information essential for precisely engineering effective immune responses.”
Can T cell depletion be reversed?
To understand how these immune states are regulated, researchers used advanced laboratory techniques, genetic tools, mouse models, and computer analysis to examine nine different CD8 T cell states. Their research has uncovered several transcription factors, proteins that regulate gene activity, and have been shown to act as switches that direct T cells toward either continued functioning or exhaustion.
Among these regulators, scientists identified two transcription factors called ZSCAN20 and JDP2 that had not previously been associated with T cell depletion. When these genes were disabled, exhausted T cells regained the ability to kill tumors while maintaining long-term immune memory.
“We asked if we could flip a specific genetic switch on T cells to restore their ability to kill tumors without compromising their ability to provide long-term immune protection,” said co-author H. Kay Chung, Ph.D., assistant professor at UNC Lineberger. Chung began this research at the Salk Institute before joining UNC. “We found that it is indeed possible to distinguish between these two results.”
These findings challenge the long-held assumption that immune depletion is an inevitable consequence of prolonged immune activity.
Manipulating more powerful immune cells for cancer treatment
The researchers say the genetic atlas they created could guide the design of more potent immune cells for treatments such as adoptive cell transfer (ACT) and CAR T-cell therapy.
“Once we have this map, we will be able to give T cells more specific instructions, helping them maintain traits that allow them to fight cancer and infection over the long term, while avoiding pathways that would burn them out,” Keck says. “By separating these two programs, we can begin to engineer immune cells that are durable and effective against cancer and chronic infections.”
This finding may be particularly important for the treatment of solid tumors, where immune depletion often limits therapeutic success.
Future strategies for AI and precision immunoengineering
In future research, the team plans to combine advanced experimental techniques with AI-guided computational modeling. Their goal is to develop a large number of more precise genetic “recipes” that can program T cells into specific functional states, improving the precision of cell therapies.
“Genes work together in complex regulatory networks that are difficult to decipher, so powerful computational tools are essential to pinpoint which regulators control specific cellular states,” said co-author Wei Wang, Ph.D., a professor at the University of California, San Diego. “This study shows that we can begin to precisely manipulate the fate of immune cells and unlock new possibilities to enhance immunotherapy.”
By revealing how killer T cells choose between resilience and fatigue, this study brings scientists closer to intentionally inducing immune responses during long-term illnesses, rather than watching them weaken.
Other authors include Eduardo Casillas, Ming Sun, Shixin Ma, Shilong Tan, Brent Chick, Victoria Triple, Brian McDonald, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H. Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, April Williams, and Diana C. Hargreaves of Salk. Cong Liu, Alexander N. Jambor, Z. Audrey Wang, Jun Wang, Zhen Wang, Jieyuan Liu, and Zhiting Hu of the University of California, San Diego; Anamika Batu, Brandon M. Platt, Fucong Shi, Brian P. Riesenberg, Elisa Landoni, Yanpei Li, Chidan Ye, Daniel Zhu, Jared Green, Zayed Said, Nolan J. Brown, Matthew Smith, Jennifer Modrzewski, Yusha Liu, Ukrae H. Cho, Giampietro Dotti, Barbara Savold, Jessica E. Thaxton, UNC’s J. Justin Milner. Peixiang He, Longwei Liu, and Yingxiao Wang of the University of Southern California; and Yiming Gao of Texas A&M University.
This study was supported by the National Institutes of Health (R37AI066232, R01AI123864, R21AI151986, R01CA240909, R01AI150282, R01HG009626, K01EB034321, R01AI177864, R01CA248359, R01CA244361, AI151123, EB029122, GM140929) and the Damon Runyon Cancer Research Foundation.
