The research, published in Nature, provides a framework that may allow scientists to deliberately program T cells so they maintain both long-term immune memory and strong cancer-fighting activity. The findings could have significant implications for cancer immunotherapy as well as treatments for infectious diseases.

CD8 killer T cells are vital to the immune system because they locate and destroy virus infected cells and cancer cells. However, when the immune system faces long lasting infections or tumors, these cells can gradually lose their effectiveness. Over time they can enter a dysfunctional condition called T cell exhaustion, where their ability to eliminate threats declines.

Building a Genetic Atlas of T Cell States

Protective T cells and exhausted ones can appear nearly identical, which makes them difficult to distinguish using traditional methods. To address this challenge, researchers explored whether these different states could be separated based on genetic activity.

A major breakthrough came from constructing a detailed genetic atlas that maps a range of CD8 T cell states. This atlas shows how these immune cells shift along a spectrum that runs from highly protective to severely impaired.

“Our long-term goal is to make immune therapies work better by creating clear ‘recipes’ for designing T cells,” says co-corresponding author Susan Kaech, PhD, a professor at the Salk Institute at the time of the study. “To do that, we first needed to identify which molecular ingredients are uniquely active in one T cell state but not others. By building a comprehensive atlas of CD8 T cell states, we were able to pinpoint the key factors that define protective versus dysfunctional programs — information that is essential for precisely engineering effective immune responses.”

Can T Cell Exhaustion Be Reversed?

To understand how these immune states are controlled, the researchers examined nine distinct CD8 T cell conditions using advanced laboratory methods, genetic tools, mouse models, and computational analysis. Their work revealed several transcription factors, proteins that regulate gene activity, which act as switches that guide T cells toward either sustained function or exhaustion.

Among these regulators, the scientists identified two transcription factors called ZSCAN20 and JDP2 that had not previously been associated with T cell exhaustion. When these genes were disabled, exhausted T cells recovered their tumor killing ability while still maintaining long-term immune memory.

“We flipped specific genetic switches in the T cells to see if we could restore their tumor-killing function without damaging their ability to provide long-term immune protection,” says co-corresponding author H. Kay Chung, PhD, an assistant professor at UNC Lineberger. Chung began this research at the Salk Institute before joining UNC. “We found that it was indeed possible to separate these two outcomes.”

These findings challenge a long-standing assumption that immune exhaustion is an unavoidable result of prolonged immune activity.

Engineering Stronger Immune Cells for Cancer Therapy

The researchers say the genetic atlas they created could help guide the design of more powerful immune cells for treatments such as adoptive cell transfer (ACT) and CAR T cell therapy.

“Once we had this map, we could start giving T cells much clearer instructions — helping them keep the traits that allow them to fight cancer or infection over the long term, while avoiding the pathways that cause them to burn out,” says Kaech. “By separating these two programs, we can begin to design immune cells that are both durable and effective in cancer and chronic infection.”

The discovery could be especially important for treating solid tumors, where immune exhaustion often limits the success of therapy.

AI and Future Strategies for Precision Immune Engineering

In future work, the team plans to combine advanced experimental techniques with AI guided computational modeling. Their goal is to develop many more precise genetic “recipes” that can program T cells into specific functional states, improving the precision of cellular therapies.

“Because genes work together in complex regulatory networks that are difficult to decipher, powerful computational tools are essential to pinpoint which regulators drive specific cell states,” says co-corresponding author Wei Wang, PhD, a professor at UC San Diego. “This study shows that we can begin to precisely manipulate immune cell fates and unlock new possibilities for enhancing immune therapies.”

By uncovering how killer T cells choose between resilience and exhaustion, the research moves scientists closer to deliberately guiding immune responses instead of watching them weaken during prolonged disease.

Other authors include Eduardo Casillas, Ming Sun, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Bryan 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 UC San Diego; Anamika Battu, Brandon M. Pratt, Fucong Xie, Brian P. Riesenberg, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J. Brown, Matthew Smith, Jennifer Modliszewski, Yusha Liu, Ukrae H. Cho, Gianpietro Dotti, Barbara Savoldo, Jessica E. Thaxton, and J. Justin Milner of UNC; Peixiang He, Longwei Liu, and Yingxiao Wang of University of Southern California; and Yiming Gao of Texas A&M University.

The work 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.