{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:05:35Z","timestamp":1785859535366,"version":"3.56.0"},"reference-count":103,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive \u201cleukemic niche.\u201d This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity.<\/jats:p>","DOI":"10.3390\/antib15040069","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T15:08:09Z","timestamp":1785856089000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Bispecific Antibodies for Acute Myeloid Leukemia: From Bone Marrow Immune Niche to Clinical Translation"],"prefix":"10.3390","volume":"15","author":[{"given":"Antonella","family":"Bruzzese","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8504-3231","authenticated-orcid":false,"given":"Enrica Antonia","family":"Martino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0698-1781","authenticated-orcid":false,"given":"Santino","family":"Caserta","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Eugenia","family":"Alvaro","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Amodio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenio","family":"Lucia","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Olivito","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Labanca","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6339-632X","authenticated-orcid":false,"given":"Francesco","family":"Mendicino","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2585-7073","authenticated-orcid":false,"given":"Fortunato","family":"Morabito","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Science, University of Calabria, 87036\u00a0Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Vigna","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5256-0726","authenticated-orcid":false,"given":"Massimo","family":"Gentile","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco-Hematology, AO of Cosenza, Viale della Repubblica snc, 87100 Cosenza, Italy"},{"name":"AIL Sezione di Cosenza, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3724","DOI":"10.1182\/blood-2010-05-282632","article-title":"Incidence of hematologic malignancies in Europe by morphologic subtype: Results of the HAEMACARE project","volume":"116","author":"Sant","year":"2010","journal-title":"Blood"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1182\/blood-2011-04-347872","article-title":"Acute leukemia incidence and patient survival among children 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