Exploring CAR cell therapies beyond CAR-T for myeloid malignancies

Chimeric antigen receptor (CAR)-T cells have demonstrated remarkable efficacy in several hematologic malignancies; however, their application in myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remains limited, with no FDA-approved products to date. This limited progress largely reflects both efficacy challenges and safety concerns. CAR-T cells demonstrate poor trafficking and persistence within the bone marrow, limited activity against leukemia stem cells (LSCs), and reliance on antigens such as CD33 and CD123 that are also expressed on normal hematopoietic stem and progenitor cells, resulting in significant on-target off-tumor toxicity. Given these limitations, attention has increasingly shifted toward alternative CAR-engineered immune cells, including CAR-natural killer (CAR-NK) cells, CAR-invariant natural killer T (CAR-NKT) cells, and CAR-macrophages (CAR-Ms). These platforms offer unique advantages, such as intrinsic antitumor activity, distinct trafficking properties, reduced risk of graft-versus-host disease (GvHD), and potentially safer antigen recognition profiles, that may help overcome barriers faced by CAR-T cells. In this review, we highlight the challenges of applying conventional CAR-T cells to myeloid malignancies, examine emerging alternative CAR-cell platforms, and discuss how their unique biology and engineering strategies may provide safer, more effective, and more accessible therapeutic options for patients with these difficult-to-treat cancers.