{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:40:20Z","timestamp":1788176420115,"version":"build-2803163510"},"reference-count":130,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is a heterogeneous and aggressive hematologic malignancy with poor prognosis despite multiple available therapies. While chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of B-cell malignancies, its application in AML has been limited by early relapses and severe toxicities. Unlike B-cell antigens, most AML-associated surface antigens are also expressed on healthy hematopoietic stem and progenitor cells, creating significant risks of on-target\/off-tumor toxicity and prolonged myeloablation. To address the scarcity of AML-specific targets, several innovative CAR strategies have been developed to enhance precision, safety, and efficacy. Logic-gated CARs improve selectivity through dual-antigen recognition or conditional activation. Drug-inducible and transient expression systems, as well as pharmacologic or suicide switches, enable controlled modulation or elimination of CAR cells to reduce toxicity. Adapter CAR platforms allow real-time, flexible targeting, while engineered modulation of gene expression or cytokine secretion enhances persistence and antitumor activity. Finally, alternative immune cells, including natural killer (NK) cells and macrophages, provide versatile platforms that may overcome limitations of conventional T-cell therapies, such as fratricide or challenges in allogeneic use. This review provides a comprehensive overview of these emerging CAR approaches, highlighting their advantages, limitations, and potential to expand immunotherapeutic strategies for AML.<\/jats:p>","DOI":"10.3390\/cancers17243892","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T13:17:07Z","timestamp":1764940627000},"page":"3892","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Rise of Fine-Tuned CAR-Based Therapies Against Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5506-0153","authenticated-orcid":false,"given":"Alejandro","family":"Segura Tudela","sequence":"first","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7612-4611","authenticated-orcid":false,"given":"Ron","family":"Geller","sequence":"additional","affiliation":[{"name":"Institute for Integrative Systems Biology (I2SysBio), Universitat de Val\u00e8ncia-CSIC, C. Catedr\u00e0tic Jos\u00e9 Beltr\u00e1n 2, 46980 Paterna, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1977-3815","authenticated-orcid":false,"given":"Bruno","family":"Paiva","sequence":"additional","affiliation":[{"name":"Clinica Universidad de Navarra (CUN), Centro de Investigacion Medica Aplicada (CIMA), Instituto de Investigacion Sanitaria de Navarra (IDISNA), CIBER-ONC Number CB16\/12\/00369, 31008 Pamplona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Carmen","family":"Torres S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Gonz\u00e1lez Romero","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6661-9631","authenticated-orcid":false,"given":"Pilar","family":"Lloret Madrid","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"},{"name":"Hematology Department, Hospital Universitari i Polit\u00e8cnic La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6741-971X","authenticated-orcid":false,"given":"Pedro","family":"Chor\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"},{"name":"Hematology Department, Hospital Universitari i Polit\u00e8cnic La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8354-768X","authenticated-orcid":false,"given":"Javier","family":"de la Rubia","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"},{"name":"Hematology Department, Hospital Universitari i Polit\u00e8cnic La Fe, 46026 Valencia, Spain"},{"name":"School of Medicine and Dentistry, Catholic University of Valencia, 46001 Val\u00e8ncia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3275-5593","authenticated-orcid":false,"given":"Pau","family":"Montesinos","sequence":"additional","affiliation":[{"name":"Hematology Department, Hospital Universitari i Polit\u00e8cnic La Fe, 46026 Valencia, Spain"},{"name":"Department of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5978-2578","authenticated-orcid":false,"given":"Manuel","family":"Guerreiro","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Sanitaria La Fe (IISLAFE), 46026 Valencia, Spain"},{"name":"Hematology Department, Hospital Universitari i Polit\u00e8cnic La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1038\/s41586-023-05707-3","article-title":"CAR Immune Cells: Design Principles, Resistance and the next Generation","volume":"614","author":"Labanieh","year":"2023","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/s41571-019-0297-y","article-title":"Engineering Strategies to Overcome the Current Roadblocks in CAR T Cell Therapy","volume":"17","author":"Rafiq","year":"2020","journal-title":"Nat. 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