{"id":55908,"date":"2026-02-04T09:00:20","date_gmt":"2026-02-04T17:00:20","guid":{"rendered":"https:\/\/www.salk.edu\/?post_type=disclosure&#038;p=55908"},"modified":"2026-03-06T10:52:10","modified_gmt":"2026-03-06T18:52:10","slug":"could-these-two-genes-make-t-cells-unstoppable","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/could-these-two-genes-make-t-cells-unstoppable\/","title":{"rendered":"\u8fd9\u4e24\u4e2a\u57fa\u56e0\u4f1a\u8ba9 T \u7ec6\u80de\u53d8\u5f97\u4e0d\u53ef\u963b\u6321\u5417\uff1f"},"content":{"rendered":"<ul>\n<li style=\"list-style: none; padding-left: -20px !important; margin-left: -20px !important;\"><strong>Highlights<\/strong><\/li>\n<li>Scientists discovered key genetic factors that determine whether a T cell acts as a powerful disease fighter or enters an ineffective, exhausted state.<\/li>\n<li>Turning off two transcription factors allowed exhausted T cells to regain their ability to kill tumors.<\/li>\n<li>The findings could help scientists engineer more powerful T cells for cellular therapies such as adoptive cell transfer (ACT) and CAR T cell therapy.<\/li>\n<\/ul>\n<p>\u62c9\u970d\u4e9a\u2014\u7531\u8428\u514b\u751f\u7269\u7814\u7a76\u6240\u3001\u5317\u5361\u7f57\u6765\u7eb3\u5927\u5b66\u6797\u4f2f\u683c\u7efc\u5408\u764c\u75c7\u4e2d\u5fc3\u548c\u52a0\u5dde\u5927\u5b66\u5723\u5730\u4e9a\u54e5\u5206\u6821\u7684\u7814\u7a76\u4eba\u5458\u7275\u5934\u7684\u4e00\u9879\u591a\u673a\u6784\u7814\u7a76\uff0c\u63ed\u793a\u4e86\u51b3\u5b9a\u514d\u75ab\u7ec6\u80de\uff0c\u5373CD8\u201c\u6740\u4f24\u6027\u201dT\u7ec6\u80de\uff0c\u5982\u4f55\u5728\u6210\u4e3a\u6301\u4e45\u7684\u4fdd\u62a4\u6027\u9632\u5fa1\u8005\u6216\u9677\u5165\u75b2\u60eb\u3001\u529f\u80fd\u5931\u8c03\u72b6\u6001\u4e4b\u95f4\u505a\u51fa\u9009\u62e9\u7684\u65b0\u9057\u4f20\u89c4\u5219\u3002\u5173\u95ed\u5176\u4e2d\u4ec5\u4e24\u4e2a\u57fa\u56e0\u5c31\u4f7f\u75b2\u60eb\u7684T\u7ec6\u80de\u6062\u590d\u4e86\u5176\u6740\u6b7b\u80bf\u7624\u7684\u80fd\u529b\u3002.<\/p>\n<figure id=\"attachment_39953\"  class=\"wp-caption alignright\"><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop.jpg\"><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"458\" class=\"img-responsive wp-image-39953 size-col-md-5\" src=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-458x458.jpg\" alt=\"Sue Kaech, PhD, led the research team based at the Salk Institute.\" srcset=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-458x458.jpg 458w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-300x300.jpg 300w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-1024x1024.jpg 1024w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-150x150.jpg 150w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-768x768.jpg 768w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-767x767.jpg 767w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-147x147.jpg 147w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-585x585.jpg 585w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-553x553.jpg 553w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-750x750.jpg 750w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-945x945.jpg 945w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-1250x1250.jpg 1250w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-400x400.jpg 400w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop-200x200.jpg 200w, https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop.jpg 1500w\" sizes=\"auto, (max-width: 458px) 100vw, 458px\" \/><\/a><figcaption class=\"wp-caption-text\">Sue Kaech, PhD, led the research team based at the Salk Institute.<br \/><a href=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-20210623-551A4420-crop.jpg\">Click here<\/a> for a high-resolution image.<br \/>Credit: Salk Institute<\/figcaption><\/figure>\n<p>The findings, published in <a href=\"https:\/\/www.nature.com\/articles\/s41586-025-09989-7\" target=\"_blank\"><em>Nature<\/em><\/a> on January 28, 2026, establish a predictive framework that can help scientists intentionally program T cells to sustain immune memory while preserving their ability to fight cancer and infections, with broad implications for cancer immunotherapy and infectious disease research.<\/p>\n<p>CD8 killer T cells play a central role in the immune system by seeking out and destroying virus-infected cells and cancer cells. However, during chronic infections or within tumors, these cells can gradually lose their killing capacity and enter an ineffective state known as T cell exhaustion.<\/p>\n<p>Protective and exhausted CD8 T cell states can look very similar, so the researchers asked whether protective immune memory and dysfunction could be distinguished on a genetic level. A key advance in the study was the creation of a detailed genetic atlas of various CD8 T cell states, capturing how these immune cells change across a spectrum from highly protective to deeply dysfunctional.<\/p>\n<p>\u201cOur long-term goal is to make immune therapies work better by creating clear \u2018recipes\u2019 for designing T cells,\u201d says co-corresponding author <a href=\"https:\/\/www.salk.edu\/zh\/scientist\/susan-kaech\/\" target=\"_blank\" rel=\"noopener\">\u82cf\u73ca-\u51ef\u5947\uff0c\u535a\u58eb<\/a>, a professor at the Salk Institute at the time of the study. \u201cTo 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\u2014information that is essential for precisely engineering effective immune responses.\u201d<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>Can T cell exhaustion ever be reversed?<\/strong><\/h2>\n<p>Using advanced laboratory techniques, genetic tools, mouse models, and computational approaches, the researchers analyzed nine distinct CD8 T cell states. They identified specific transcription factors\u2014proteins that control gene activity\u2014that act like molecular switches, steering T cells toward either long-term function or exhaustion.<\/p>\n<p>Among these, the team discovered two transcription factors, ZSCAN20 and JDP2, that had not previously been linked to T cell exhaustion. When the researchers turned these factors off, exhausted T cells regained their ability to kill tumors without losing their capacity for long-term immune memory.<\/p>\n<p>\u201cWe 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,\u201d 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. \u201cWe found that it was indeed possible to separate these two outcomes.\u201d<\/p>\n<p>The study challenges the long-standing belief that immune exhaustion is an unavoidable consequence of prolonged immune activity.<\/p>\n<h2 style=\"font-size: 20px; margin-top: 40px;\"><strong>Can T cells be engineered to prevent burnout?<\/strong><\/h2>\n<p>The researchers say this genetic atlas of T cell states could now guide the development of supercharged T cells for use in cellular therapies such as adoptive cell transfer (ACT) and CAR T cell therapy.<\/p>\n<p>\u201cOnce we had this map, we could start giving T cells much clearer instructions\u2014helping 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,\u201d says Kaech. \u201cBy separating these two programs, we can begin to design immune cells that are both durable and effective in cancer and chronic infection.\u201d<\/p>\n<p>The researchers say the findings should be especially relevant for treating solid tumors, where separating protective immune responses from exhaustion is critical for effective therapy.<\/p>\n<p>Looking ahead, the team will combine advanced laboratory methods with AI-guided computational modeling to develop a larger number of precise genetic recipes for programming T cells into specific states, enabling greater precision for cellular therapies.<\/p>\n<p>\u201cBecause 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,\u201d says co-corresponding author Wei Wang, PhD, a professor at UC San Diego. \u201cThis study shows that we can begin to precisely manipulate immune cell fates and unlock new possibilities for enhancing immune therapies.\u201d<\/p>\n<p>By revealing how killer T cells choose between resilience and burnout, this research brings scientists closer to guiding the immune system with intention\u2014rather than watching it fail under pressure.<\/p>\n<p>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&amp;M University.<\/p>\n<p>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.<\/p>","protected":false},"featured_media":39959,"template":"","faculty":[311],"disease-research":[46,332,122,366],"class_list":["post-55908","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-susan-kaech","disease-research-cancer-biology","disease-research-computational-biology","disease-research-immune-system-biology","disease-research-infectious-disease"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Could these two genes make T cells unstoppable? - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/could-these-two-genes-make-t-cells-unstoppable\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Could these two genes make T cells unstoppable? - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"Highlights Scientists discovered key genetic factors that determine whether a T cell acts as a powerful disease fighter or enters an ineffective, exhausted state. Turning off two transcription factors allowed exhausted T cells to regain their ability to kill tumors. The findings could help scientists engineer more powerful T cells for cellular therapies such as adoptive cell transfer (ACT) and CAR T cell therapy. LA JOLLA\u2014A multi-institutional study led by researchers at the Salk Institute for Biological Studies, UNC Lineberger Comprehensive Cancer Center, and UC San Diego has uncovered new genetic rules that determine how immune cells, known as CD8 \u201ckiller\u201d T cells, choose between becoming long-lasting, protective defenders or slipping into exhausted, dysfunctional states. Turning off just two of these genes allowed exhausted T cells to regain their tumor-killing capacity.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.salk.edu\/zh\/news-release\/could-these-two-genes-make-t-cells-unstoppable\/\" \/>\n<meta property=\"og:site_name\" content=\"Salk Institute for Biological Studies\" \/>\n<meta property=\"article:modified_time\" content=\"2026-03-06T18:52:10+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.salk.edu\/wp-content\/uploads\/2023\/04\/Sue-Kaech-767.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"767\" \/>\n\t<meta property=\"og:image:height\" content=\"767\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data1\" content=\"5 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/could-these-two-genes-make-t-cells-unstoppable\\\/\",\"url\":\"https:\\\/\\\/www.salk.edu\\\/news-release\\\/could-these-two-genes-make-t-cells-unstoppable\\\/\",\"name\":\"Could these two genes make T cells unstoppable? 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Kay Chung, Cong Liu, Anamika Battu, Alexander N. Jambor, Brandon M. Pratt, Fucong Xie, Brian P. Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J. Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z. Audrey Wang, Jun Wang, Bryan McDonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H. Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H. Cho, Longwei Liu, Yingxiao Wang, Diana C. Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E. Thaxton, J. Justin Milner, Susan M. 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