The search for safe and effective CAR-T targets in AML.

Acute myeloid leukemia (AML) remains a highly aggressive malignancy with limited therapeutic options and poor long-term survival. A major barrier to curative treatment is the persistence of leukemic stem cells (LSCs), a chemo-resistant population that drives relapse. Chimeric antigen receptor (CAR)-T-cell therapy has transformed the treatment of B-cell hematological malignancies. However, its application in AML has been met with significant challenges. Among the key challenges are the scarcity of AML-specific antigens and the risk of on-target/off-tumor toxicity due to shared antigen expression on normal hematopoietic stem cells (HSCs) and/or mature blood cells. Early clinical trials of CAR-T-cell therapy in AML -primarily targeting CD123, CD33, or CLL‑1- have demonstrated limited durable complete remissions and/or frequent myeloablation, underscoring the need for more selective targets. While other targets show more restricted expression profiles, they are often expressed only in a small subgroup of AML patients. In this review, we systematically evaluated 63 AML-associated antigens for which CAR constructs have been reported, using five criteria: (1) homogeneous expression across AML patients, (2) uniform expression on AML cells within individual patients; (3) presence on LSCs, (4) absence on normal HSCs, and (5) no or acceptable expression on mature blood cells. Applying a 20-point scoring framework, 13 novel antigens emerged as the most promising candidates for CAR-T-cell therapy in AML: ADGRE2, SIGLEC-6, IL1RAP, MUC1, CCR1, CD155, CD70, LILRB4, GRP78, CD37, ITGB2, TIM-3 and mesothelin. We discuss the advantages and limitations of each target, along with strategies to mitigate associated risks. With no CAR-T-cell therapy currently approved for AML, this comprehensive review provides a prioritized antigen landscape and a framework to guide the rational design of next-generation CARs for this challenging malignancy.