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Hypomethylating agents (HMAs) such as azacitidine and decitabine can reverse abnormal DNA methylation, promote leukemic cell differentiation, and enhance immune recognition, yet relapse and therapeutic resistance remain major challenges. In this study, we found that long-term, low-dose HMA treatment upregulated CD70, NK receptor ligands, and CD1d on AML tumor cells, rendering them more susceptible to chimeric antigen receptor (CAR)-engineered invariant natural killer T (CAR-NKT) cell-mediated cytotoxicity. To exploit these features, we generated two types of CD70-targeting CAR-NKT cells: cord blood hematopoietic stem and progenitor cell (HSPC)-derived allogeneic CAR70-NKT (\n                    <jats:sup>Allo<\/jats:sup>\n                    CAR70-NKT) cells and peripheral blood mononuclear cell (PBMC)-derived CAR70-NKT (\n                    <jats:sup>PBMC<\/jats:sup>\n                    CAR70-NKT) cells. Both CAR70-NKT cell products exhibited potent cytotoxicity against AML cells and synergized with HMAs, while\n                    <jats:sup>Allo<\/jats:sup>\n                    CAR70-NKT cells demonstrated superior antitumor efficacy, multi-target recognition, and sustained expansion. In multiple xenograft models,\n                    <jats:sup>Allo<\/jats:sup>\n                    CAR70-NKT cells effectively killed AML tumors without inducing graft-versus-host disease, cytokine release syndrome, or long-term organ toxicity. These findings highlight\n                    <jats:sup>Allo<\/jats:sup>\n                    CAR70-NKT cells as a safe and powerful off-the-shelf immunotherapy that can synergize with HMAs to improve treatment outcomes for patients with AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02930-5","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T08:33:26Z","timestamp":1774514006000},"page":"880-893","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Synergizing hypomethylating agents with off-the-shelf CD70-targeted chimeric antigen receptor-engineered natural killer T cells for the treatment of acute myeloid leukemia"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9858-300X","authenticated-orcid":false,"given":"Yan-Ruide","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yichen","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caspian","family":"Oliai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6568-0404","authenticated-orcid":false,"given":"Lili","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,26]]},"reference":[{"key":"2930_CR1","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41571-021-00509-w","volume":"18","author":"H D\u00f6hner","year":"2021","unstructured":"D\u00f6hner H, Wei AH, L\u00f6wenberg B. 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None of the declared companies contributed to or directed any of the research reported in this article. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with approved guidelines from the University of California, Los Angeles (Reference: BUA-2019-083-017-A). Animal studies were conducted under protocols approved by the UCLA Division of Laboratory Animal Medicine (ARC#2013-054). Healthy donor PBMCs were obtained from the UCLA\/CFAR Virology Core Laboratory and HemaCare under informed consent and in compliance with federal and state regulations; no identifying information was provided.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}