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

## TL;DR

This study identifies cell-surface chaperones in AML cells as potential targets for CAR immunotherapy, offering a new precision treatment approach.

## Contribution

The study discovers that chronic ER stress in AML cells leads to cell-surface chaperones, which can be targeted by CAR-NK cells for precision immunotherapy.

## Key findings

- ER chaperones like HSP90B1 and P4HB translocate to the cell surface in AML cells under chronic ER stress.
- CAR-NK cells targeting HSP90B1 show selective cytotoxicity against AML cells in vitro and in animal models.
- These chaperones are proposed as neoantigens for AML classification and immunotherapy.

## 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.

Acute myeloid leukemia (AML) remains a therapeutic challenge due to its heterogeneity and limited targets. Here, multi‐omics analyses are utilized, and it is revealed that AML cells, particularly the FLT3‐ITD+ subtype, undergo chaperone‐mediated ER stress, inducing surface translocation of ER chaperones. Subsequently, CAR‐NK cells targeting these chaperone proteins are engineered, demonstrating specific anti‐leukemia efficacy in vitro and in vivo, which offers a novel immunotherapeutic strategy for precision AML treatment.