{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T06:38:00Z","timestamp":1777012680647,"version":"3.51.4"},"reference-count":316,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T00:00:00Z","timestamp":1776988800000},"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>\n                    Hematologic disorders, including malignant and autoimmune conditions, present persistent clinical challenges characterized by relapse, treatment resistance, and profound immune dysregulation. While conventional immunotherapies have advanced, their efficacy is frequently limited by HLA downregulation and effector T cell exhaustion. In this context, \u03b3\u03b4 T cells offer a promising therapeutic alternative. Recognizing antigens independently of MHC restriction, \u03b3\u03b4 T cells possess intrinsic tissue-homing capabilities and exhibit dual cytotoxic and immunoregulatory functions. These properties make them highly suitable candidates for allogeneic, \u201coff-the-shelf\u201d cellular therapies where \u03b1\u03b2 T cells face alloreactive limitations. This review systematically synthesizes the immunobiology of \u03b3\u03b4 T cells, exploring the functional heterogeneity of specific subsets and their regulation within the tumor microenvironment (TME). We critically evaluate recent preclinical and clinical evidence supporting adoptive transfer, CAR-\u03b3\u03b4 T strategies, and combination regimens across acute leukemias, lymphomas, multiple myeloma, and immune cytopenias. Furthermore, we address critical translational barriers\u2014including\n                    <jats:italic>in vivo<\/jats:italic>\n                    persistence, subset exhaustion, and manufacturing variability\u2014and discuss rational engineering strategies, metabolic preconditioning, and epigenetic modulation as solutions. Ultimately, advancing \u03b3\u03b4 T cell therapies requires overcoming these hurdles to transition them effectively from the bench to mainstream clinical practice.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1775981","type":"journal-article","created":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T05:42:33Z","timestamp":1777009353000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Translational potential of \u03b3\u03b4 T cells in hematologic diseases: from immunobiology to therapeutic innovation"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaokuan","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang","place":["Liaoning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengqi","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang","place":["Liaoning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang","place":["Liaoning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guojun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, The Fourth Affiliated Hospital of China Medical University, Shenyang","place":["Liaoning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27448","article-title":"2025 update on clinical trials in immune thrombocytopenia","volume":"99","author":"Al-Samkari","year":"2024","journal-title":"Am J 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