{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:23:19Z","timestamp":1793643799248,"version":"4.5.1"},"reference-count":86,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Chimeric antigen receptor T-cell (CAR-T) therapy has achieved impressive remission rates in hematologic cancers, but long-term efficacy remains limited by insufficient CAR-T cell persistence. T cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1), transcription factors well known for their role in downstream Wnt\/\u03b2-catenin signaling, have been found to regulate transcriptional and epigenetic memory programming important for CAR-T cell persistence and favorable patient outcomes. Activation of the Wnt\/\u03b2-catenin in endogenous T cells was found to arrest effector differentiation and promote the formation of cluster of differentiation (CD) 8+ memory stem cells, characterized by strong proliferative and recall potential, key traits of persisting memory cells. Genetically engineered CAR-T cells are subject to the same transcriptional and epigenetic factors that govern memory development in endogenous T cells, providing a strong rationale for applying scientific findings from basic T cell biology to CAR-T cell engineering. With this in mind, recent studies have shown that there is clinical potential for Wnt-directed approaches to improve CAR-T cell memory phenotypes, persistence, and exhaustion. Here we review the role of Wnt\/\u03b2-catenin signaling in T cell development and memory formation, examine clinical evidence linking Wnt\/TCF1 activity to CAR-T cell persistence and patient outcomes, and discuss emerging genetic, epigenetic, and pharmacological strategies used to target this pathway in CAR-T cell manufacturing.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1843548","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:50:25Z","timestamp":1778647825000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Tatiana","family":"Fourfouris","sequence":"first","affiliation":[{"name":"Kim Lab, Children\u2019s Hospital Los Angeles, Department of Pediatrics, Division of Hematology and Oncology, Keck School of Medicine, University of Southern 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