{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T03:26:02Z","timestamp":1784949962694,"version":"3.55.0"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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>The tumor microenvironment (TME) in hematologic malignancies constitutes a dynamic ecosystem supporting leukemogenesis, therapeutic resistance, and immune evasion. Key drivers of this immunosuppressive network are regulatory T cells (Tregs), a CD4+ subset conventionally defined by FoxP3 and CD25 expression. While physiological Tregs are essential for self-tolerance, leukemic blasts frequently co-opt these cells to dampen anti-tumor immunity. Here, we review the distinct roles of Tregs across the spectrum of leukemias, including Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic Lymphocytic Leukemia (CLL). We dissect the molecular machinery governing Treg recruitment and suppression within the bone marrow niche, highlighting the CCL22\/CCR4 axis, metabolic reprogramming via the CD39\/CD73 adenosine pathway, and indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan catabolism. Additionally, we critically evaluate the nuanced and often discordant prognostic impact of Treg infiltration across different subtypes. A significant portion of this review examines the evolving therapeutic landscape, scrutinizing Treg-depleting antibodies (e.g., mogamulizumab, RG6292), immunomodulatory small molecules (venetoclax, hypomethylating agents, TKIs), and the challenges Tregs pose to cellular therapies. Finally, we discuss novel strategies to circumvent Treg-mediated resistance, offering a perspective on restoring anti-leukemic immunity.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1822997","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:47:51Z","timestamp":1779256071000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["The evolving landscape of regulatory T cells in leukemia: from mechanisms to advanced immunotherapeutic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Huili","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Hematology, Pingdingshan First People\u2019s Hospital","place":["Pingdingshan, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Pingdingshan First People\u2019s Hospital","place":["Pingdingshan, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Pingdingshan First People\u2019s Hospital","place":["Pingdingshan, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-365817","article-title":"Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation","volume":"118","author":"Ustun","year":"2011","journal-title":"Blood"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1530301","article-title":"Recent advances in regulatory immune cells: exploring the world beyond Tregs","volume":"16","author":"Shi","year":"2025","journal-title":"Front Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1049301","article-title":"Regulation of 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