UCSD - University of California - San Diego

02/04/2026 | Press release | Distributed by Public on 02/04/2026 10:02

Blueprints for Designing T Cells that Kill

Published Date

February 04, 2026

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A multi-institution study led by researchers at University of California San Diego, the Salk Institute for Biological Studies and the University of North Carolina at Chapel Hill has mapped the internal genetic programs that determine the behavior of powerful white blood cells, called CD8 killer T cells, which are critical for controlling infections and fighting cancer. These cells take on different states depending on their environment, and these cell states can determine how well cancers respond to immunotherapy. Understanding how different cell states arise could help make these treatments more effective and targeted. The findings are published in Nature.

"This study shows that we can begin to precisely manipulate immune cell fates and unlock new possibilities for enhancing immune therapies," said co-corresponding author Wei Wang, PhD, a professor in the Departments of Cellular and Molecular Medicine and Biochemistry and Molecular Biophysics at UC San Diego. Additional co-corresponding authors on the study include Susan M. Kaech, PhD, at the Salk Institute, and H. Kay Chung, PhD, at UNC Lineberger Comprehensive Cancer Center.

Because protective and dysfunctional CD8 T cell states can look very similar, we designed this study to ask whether protective immune memory and dysfunction could be genetically separated. Wwe 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," said Chung. "We found that it was indeed possible to separate these two outcomes."

The role of CD8 killer T cells is to seek out and destroy virus-infected cells and cancer cells. During chronic viral infections or within tumors, CD8 T cells can gradually lose their killing ability and enter a state known as T cell exhaustion, in which they become dysfunctional and ineffective. Using advanced lab, gene, mouse and computational approaches, the researchers analyzed nine distinct CD8 T cell states that spanned a spectrum from protective to dysfunctional.

"This is a challenging task", said Wang. "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."

The researchers identified specific transcription factors - proteins that control gene activity - that act like switches to direct killer T cells into different functional states. Specifically, they discovered new exhausted-state transcription factors (ZSCAN20 and JDP2) that had no known prior function in T cells. When these factors were turned off, exhausted T cells regained their ability to kill tumors without losing their capacity for long-term immune memory.

"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," Kaech said.

The researchers will next use advanced laboratory techniques and AI-guided computational modeling to develop precise genetic "recipes" for programming killer T cells-directing them toward beneficial, long-lasting states while actively avoiding dysfunctional ones. This level of precision is essential for advancing therapeutic approaches where immune cells are modified and returned to patients, such as adoptive cell transfer therapy, which involves expanding a patient's own tumor-fighting T cells outside the body and reinfusing them to boost their ability to attack cancer, and chimeric antigen receptor therapy, which engineers T cells with synthetic receptors that help them recognize and kill cancer cells more effectively.

"It is important to emphasize that this work was truly a team effort," Chung said. "It began with the synergy between Dr. Kaech's immunology lab at Salk and Dr. Wang's computational platform at UC San Diego, and after my move to UNC, collaborations here allowed us to strengthen and extend the findings."

Read the full study.

Additional co-authors on the study include Cong Liu, Alexander N. Jambor, Z. Audrey Wang, Jun Wang, Peixiang He, Longwei Liu, Zhen Wang, Jieyuan Liu and Zhiting Hu at UC San Diego; Eduardo Casillas, Ming Sun, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Josephine Ho, Diana C. Hargreaves and April Williams at the Salk Institute for Biological Studies; Anamika Battu, Brandon M. Pratt, Brian P. Riesenberg, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J. Brown, Matthew Smith, Ukrae H. Cho, Gianpietro Dotti, Barbara Savoldo and J. Justin Milner at University of North Carolina; and Yiming Gao at Texas A&M University.

The study was funded, in part, by grants from the National Institutes of Health (R37AI066232, R01AI123864, R21AI151986, R01CA240909, R01AI150282, R01HG009626, K01EB034321, R01AI177864, R01CA248359, R01CA244361, AI151123, EB029122 and GM140929).

Disclosures: Susan M. Kaech is an SAB member for Pfizer, EvolveImmune Therapeutics, Arvinas and Affini-T, advisor for Barer Institute of Raphael Holdings and academic editor at Journal of Experimental Medicine. The remaining authors declare no conflict of interest.

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