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This underscores the urgent need to identify specific targets for precision medicine. Here, multi\u2010omics approaches are utilized and discover that AML cells undergo chaperone\u2010mediated chronic endoplasmic reticulum (ER) stress. Through integrative analyses of single\u2010cell RNA\u2010seq, cell\u2010surface proteomes, and cellular biology, ER chaperone proteins (e.g., HSP90B1 and P4HB) are identified as potential neoantigens that translocate to the cell surface upon chronic ER stress. These results suggest that these proteins, especially in FLT3\u2010ITD\n                    <jats:sup>+<\/jats:sup>\n                    AML cells, show great promise as diagnostic markers and therapeutic targets. To explore the therapeutic potential, chimeric antigen receptor\u2013natural killer (CAR\u2010NK) cells targeting surface\u2010localized HSP90B1 are engineered. These engineered cells show selective cytotoxicity both in vitro and in animal models. This study not only identifies neoantigens as specific biomarkers refining AML classification, but also emphasizes the potential of immunotherapy\u2010based precision treatments for AML.\n                  <\/jats:p>","DOI":"10.1002\/advs.202511573","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T10:45:43Z","timestamp":1761216343000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chronic ER Stress Triggers Cell\u2010Surface Chaperones as the Therapeutic Targets of CAR Cells in Acute Myeloid Leukemia"],"prefix":"10.1002","volume":"13","author":[{"given":"Yimin","family":"Zhou","sequence":"first","affiliation":[{"name":"Institute of Biomedical Research Yunnan University  Kunming Yunnan 650500 China"},{"name":"State Key Laboratory of Organ Regeneration and Reconstruction Institute of Zoology Chinese Academy of Sciences  Beijing 100101 China"},{"name":"Beijing Institute for Stem 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