CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies

Chimeric antigen receptor T (CAR-T) cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, its clinical application is limited by toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and graft-versus-host disease. Natural killer (NK) cells, as key components of the innate immune system, can directly recognize and eliminate tumor cells without prior antigen sensitization. Capitalizing on their inherent allogeneic compatibility and potential for off-the-shelf use, chimeric antigen receptor NK (CAR-NK) cell therapy has emerged as a promising alternative to CAR-T strategies. Despite their potent antitumor activity in hematologic cancers, CAR-NK cells face several challenges: the need for optimized CAR designs, limited in vivo persistence and expansion, functional suppression by the immunosuppressive tumor microenvironment, as well as issues of antigen evasion, fratricide, host immune rejection, and scalable manufacturing. This review systematically summarizes recent advances in CAR-NK cell therapy for hematologic malignancies and outlines strategies to enhance its efficacy. These strategies include novel CAR designs, improved persistence and expansion, modulation of the immunosuppressive tumor microenvironment, and synergistic combination therapies. We also address the prevention of antigen evasion, fratricide, and host rejection—topics less comprehensively covered in prior reviews. Additionally, we examine the optimization of cell sources and manufacturing processes, with particular emphasis on emerging platforms for cell sorting and cryopreservation that have received limited attention. Furthermore, we discuss the current clinical landscape of CAR-NK cells and potential future strategies for optimizing clinical application. Together, these advances highlight the significant translational potential of CAR-NK cell therapy, a platform strengthened by its favorable safety profile and encouraging antitumor activity for treating hematologic malignancies.