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Resistance is driven in part by the genetic heterogeneity of AML, most notably\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations, present in 10\u201315% of de novo and up to 25% of therapy-related AML. Thus, we hypothesized that\n                    <jats:italic>TP53<\/jats:italic>\n                    aberrations in AML contribute to cell-intrinsic and extrinsic resistance against T-cell-based immunotherapy. Cytotoxicity against\n                    <jats:italic>TP53<\/jats:italic>\n                    -deleted (DEL) primary AML cells and\n                    <jats:italic>TP53<\/jats:italic>\n                    -knockdown (KD) AML cell lines was reduced in co-cultures with T cells stimulated with the BiTE molecule AMG 330 (CD3\u00d7CD33). In addition, T-cell proliferation and proinflammatory cytokine secretion was impaired in co-cultures with\n                    <jats:italic>TP53<\/jats:italic>\n                    KD cells. Transwell assays identified the secretome of\n                    <jats:italic>TP53<\/jats:italic>\n                    KD AML cells as a key contributor to the immunosuppressive effects. Proteomic analysis revealed TGF-\u03b21 in TP53 KD co-cultures as a mediator of T-cell suppression. RNA sequencing of T cells co-cultured with\n                    <jats:italic>TP53<\/jats:italic>\n                    KD cells uncovered a transcriptional shift toward a senescent cell cycle profile. Our data collectively identify the immunosuppressive secretome of\n                    <jats:italic>TP53<\/jats:italic>\n                    -deficient AML as a key barrier to T-cell-engaging immunotherapies, underscoring an unmet clinical need for strategies able to restore T-cell function in\n                    <jats:italic>TP53<\/jats:italic>\n                    KD AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02991-6","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T07:46:11Z","timestamp":1780299971000},"page":"1624-1635","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["TP53 deficiency in AML induces resistance to T-cell engagers through an immunosuppressive 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SK has received honoraria from Cymab, Plectonic, TCR2 Inc, Galapagos, Novartis, Regeneron, BMS, Miltenyi, and GSK. SK is an inventor of several patents in the field of immuno-oncology. SK received license fees from TCR2 Inc. and Carina Biotech. SK received research support from TCR2 Inc., Tabby Therapeutics, Catalym GmbH, Plectonic GmbH, and Arcus Bioscience for work unrelated to the manuscript. RK has stock ownership in Amgen Inc. VB has received research funding from Gilead\/Kite and Miltenyi Biotec; educational grants from BMS, Novartis, Takeda, and Roche; served as a consultant\/advisor for Amgen, Gilead\/Kite, Novartis, Pfizer, and Priothera; and serves on the speaker\u2019s bureau for Novartis and Pfizer.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors confirm that all methods were performed in accordance with the relevant guidelines and regulations. All human samples were collected with written informed consent in accordance with the Declaration of Helsinki and approval by the Institutional Review Board of the LMU Munich. All in vivo experiments were approved and performed in accordance with the guidelines implemented by the Regierung von Oberbayern.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}