Immunological barriers and engineering strategies for CAR-T cell therapy in acute myeloid leukemia.

Acute myeloid leukemia (AML) remains a difficult disease to treat, especially in patients with relapsed or refractory disease. While chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape of several B-cell malignancies, its clinical efficacy in AML has been substantially more limited. This limited efficacy reflects not only challenges in CAR design, but also the complex biological and immunological barriers inherent to AML. Insufficient target specificity, pronounced leukemic heterogeneity, and an immunosuppressive bone marrow microenvironment collectively impair CAR-T cell recognition, persistence, and effector function, thereby restricting both therapeutic efficacy and safety. In this review, we discuss these major barriers and summarize emerging engineering strategies developed to address them, including approaches to improve targeting precision, reinforce CAR-T cell functional fitness, and remodel the suppressive immune niche. Together, these insights may help clarify the key barriers to effective CAR-T therapy in AML and inform future strategies for its optimization.