Expanding the frontier of CAR therapy: comparative insights into CAR-T, CAR-NK, CAR-M, and CAR-DC approaches.

Chimeric antigen receptor (CAR) therapies have demonstrated remarkable clinical efficacy in hematological malignancies, validating their therapeutic potential. However, challenges such as therapeutic resistance and limited accessibility hinder their broader application. To overcome these limitations, alternative CAR-based cell therapies, including CAR-Natural Killer (CAR-NK), CAR-macrophage (CAR-M), and CAR-dendritic cell (CAR-DC) therapies, have been proposed. Compared with CAR-T, CAR-NK cells have a higher safety profile in terms of cytokine release syndrome (CRS) and neurotoxicity, while being naturally cytotoxic, making them a promising option. Despite these advantages, CAR-NK therapy is limited by issues such as insufficient tissue infiltration and low transduction efficiency. CAR-M cells, with their potent infiltration capabilities and ability to function as antigen-presenting cells, also hold promise but face challenges related to suboptimal viral transduction efficiency. CAR-DCs are emerging as a highly promising approach and are currently undergoing active investigation. This review summarizes the profiles, current clinical trials, and comparative advantages and limitations of CAR-T, CAR-NK, CAR-M, and CAR-DC therapies. Finally, we discuss the key challenges to be addressed and the future prospects of these evolving CAR-based cell therapies.