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Existing chimeric antigen receptor T cell (CAR-T) strategies are limited by toxicity and complex manufacturing, underscoring the need for transient, controllable, and safe CAR-engineering platforms that can selectively target multidrug-resistant (MDR) AML cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed a lipid nanoparticle (LNP)\u2013based mRNA delivery platform for scalable generation of C-type lectin-like molecule-1 (CLL-1) CAR-NK cells. NK phenotype, cytotoxicity, cytokine secretion, and safety were evaluated ex vivo against AML cell lines and patient-derived blasts, with in vivo efficacy tested in xenograft NSG mouse models. Mechanisms of adaptive resistance were investigated through transcriptomic profiling, modulation of the NKG2A\/HLA-E axis, and functional interrogation of the JAK2\u2013STAT1 signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Drug-response profiling across AML cohorts identified a multidrug-resistant subgroup marked by a distinct transcriptomic program in which CLL-1 was the only validated CAR target upregulated. mRNA\u2013LNP transfection enabled efficient generation of primary CLL-1 CAR-NK cells with preserved phenotype and potent, antigen-specific cytotoxicity against AML cells, while sparing normal hematopoietic progenitors. In vivo, repeated CAR-NK infusions markedly suppressed leukemia progression and prolonged survival. Transcriptomic analyses of tumor cells surviving CAR-NK exposure revealed inflammatory activation with progressive HLA-E upregulation, which impaired CAR-NK function. NKG2A blockade restored cytotoxicity ex vivo and enhanced leukemia clearance and survival in vivo. Mechanistically, prolonged CAR-NK engagement or IFN-\u03b3 stimulation activated a JAK2\u2013STAT1 axis that drove sustained HLA-E induction. JAK2 knockdown reduced HLA-E expression and sensitized AML cells to CAR-NK\u2013mediated killing, whereas pharmacologic JAK2 inhibition also decreased HLA-E expression but concurrently impaired NK-cell activation, thereby limiting the overall therapeutic benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Transient, non-integrating mRNA\u2013LNP\u2013transfected CLL-1 CAR-NK cells provide a safe and effective strategy for MDR AML. Repeated dosing enables robust antitumor activity, while adaptive resistance via NKG2A\/HLA-E axis can be mitigated through checkpoint blockade. The JAK2\u2013STAT1 pathway represents a potential upstream modulator, providing opportunities for rational combinatorial approaches to optimize CAR-NK therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03689-4","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T14:34:54Z","timestamp":1773758094000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Engineering CLL-1 CAR-NK cells via mRNA\u2013LNP for potent antitumor activity and reversal of HLA-E\u2013mediated resistance in acute myeloid leukemia"],"prefix":"10.1186","volume":"45","author":[{"given":"Jie","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yebing","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rufang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongming","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"issue":"5","key":"3689_CR1","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1002\/ajh.27625","volume":"100","author":"S Shimony","year":"2025","unstructured":"Shimony S, Stahl M, Stone RM. 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