Chronic ER Stress Triggers Cell‐Surface Chaperones as the Therapeutic Targets of CAR Cells in Acute Myeloid Leukemia

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy with low survival rates, primarily due to its inherent complexity. This underscores the urgent need to identify specific targets for precision medicine. Here, multi‐omics approaches are utilized and discover that AML cells undergo chaperone‐mediated chronic endoplasmic reticulum (ER) stress. Through integrative analyses of single‐cell RNA‐seq, cell‐surface 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‐ITD + AML cells, show great promise as diagnostic markers and therapeutic targets. To explore the therapeutic potential, chimeric antigen receptor–natural killer (CAR‐NK) cells targeting surface‐localized 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‐based precision treatments for AML.