Unlocking the Potential of CAR-NK Cell Therapy: Overcoming Barriers and Challenges in the Treatment of Myeloid Malignancies

Abstract Myeloid malignancies include various types of cancers that arise from abnormal development or proliferation of myeloid cells within the bone marrow. Chimeric antigen receptor (CAR) T cell treatments, which show great potential for B cell and plasma cell cancers, face major challenges when used for myeloid malignancies. CAR natural killer (NK) cell-based immunotherapy encounters several challenges in treating myeloid cancers, including: (1) poor gene transfer efficiency and expansion platforms in vitro, (2) limited proliferation and persistence in vivo, (3) antigenic heterogeneity, and (4) an immunosuppressive tumor microenvironment. Despite these hurdles, "off-the-shelf" CAR-NK treatments showed encouraging results, marked by enhanced proliferation, prolonged persistence, enhanced tumor infiltration, and improved adaptability. This review offers a summary of the biological traits and cellular sources of NK cells along with a discussion of contemporary CAR designs. Furthermore, it addresses the challenges observed in preclinical research and clinical trials of CAR-NK cell therapy for myeloid cancers, suggesting enhancement strategies.