{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:01:34Z","timestamp":1781103694747,"version":"3.54.1"},"reference-count":59,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["DV1-197666"],"award-info":[{"award-number":["DV1-197666"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012118","name":"Ontario Institute for Cancer Research","doi-asserted-by":"publisher","award":["IA-039"],"award-info":[{"award-number":["IA-039"]}],"id":[{"id":"10.13039\/100012118","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Longo Family Cancer Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100009812","name":"Princess Margaret Cancer Foundation","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100009812","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Amgen Chair in Cancer Research","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,4,28]]},"abstract":"<jats:p>\n                    Adoptive T cell therapies typically rely on ex vivo CD3\/CD28 stimulation, which promotes effector differentiation and limits the persistence of transferred cells. Stem cell\u2013like memory T cells (Tscm), with their capacity for self-renewal and multipotency, represent an ideal therapeutic subset but remain difficult to generate at scale. Here, we present a CD3-independent strategy using artificial antigen-presenting cells expressing a membrane-bound CD28 superagonist (\u03b1CD28-aAPCs) to expand CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells with Tscm-like features. In na\u00efve CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, \u03b1CD28-aAPC stimulation initiates a distinct transcriptional and epigenetic program, marked by high TCF1 expression, metabolic fitness, and resistance to exhaustion\u2014key hallmarks of the Tscm phenotype. Mechanistically, this approach circumvents canonical CD3\/TCR signaling and notably avoids induction of IRF4, a key transcription factor that drives BLIMP1 upregulation, TCF1 downregulation, and glycolytic commitment during effector differentiation. Instead, sustained CD28 signaling alone reprograms T cells toward a Tscm-like state. Upon subsequent antigen encounter and CD3 engagement, these \u03b1CD28-aAPC-expanded T cells mount robust effector responses while retaining superior persistence and antitumor activity in preclinical models. Our findings reveal an underappreciated role of CD28 signaling in guiding Tscm-like fate through IRF4 suppression and establish a platform for generating durable and functionally potent T cell therapies.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2524626123","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T16:25:41Z","timestamp":1776788741000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["CD28-driven ex vivo generation of stem-like memory CD8\n                    <sup>+<\/sup>\n                    T cells bypassing CD3\/TCR signaling"],"prefix":"10.1073","volume":"123","author":[{"given":"Fumie","family":"Ihara","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yota","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]},{"name":"Department of Immunology, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evey Y. F.","family":"Zheng","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]},{"name":"Department of Immunology, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Fukao","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rowena","family":"Rodrigo","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak","family":"Noamani","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giselle 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Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Burt","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayoko","family":"Saso","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalam","family":"Ly","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kagoya","sequence":"additional","affiliation":[{"name":"Division of Tumor Immunology, Institute for Advanced Medical Research, Keio University","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus O.","family":"Butler","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]},{"name":"Department of Immunology, University of Toronto","place":["Toronto, Canada"]},{"name":"Department of Medicine, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6766-861X","authenticated-orcid":false,"given":"Tak W.","family":"Mak","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]},{"name":"Department of Immunology, University of Toronto","place":["Toronto, Canada"]},{"name":"Centre for Oncology and Immunology, Hong Kong Science Park","place":["Hong Kong Special Administrative Region, China"]},{"name":"Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong","place":["Hong Kong Special Administrative Region, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D.","family":"Saibil","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network","place":["Toronto, Canada"]},{"name":"Department of Immunology, University of Toronto","place":["Toronto, Canada"]},{"name":"Department of Medicine, University of Toronto","place":["Toronto, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9070-4754","authenticated-orcid":false,"given":"Naoto","family":"Hirano","sequence":"additional","affiliation":[{"name":"Princess Margaret 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