Natural killer cell-based immunotherapy for cancer

Natural killer (NK) cells are emerging as a promising tool for cancer immunotherapy due to their innate ability to selectively recognize and eliminate cancer cells. Over the past 3 decades, strategies to harness NK cells have included cytokines, small molecules, antibodies, and the adoptive transfer of autologous or allogeneic NK cells, both unmodified and genetically engineered. Despite favorable safety profiles in clinical trials, challenges such as limited in vivo persistence, exhaustion, and the suppressive tumor microenvironment continue to hinder their efficacy and durability. This review categorizes NK cell-based therapies into 3 major approaches: (i) cellular therapies, including unmodified and chimeric antigen receptor-engineered NK cells; (ii) cytokine-based strategies such as interleukin-2 and interleukin-15 derivatives; and (iii) antibody-based therapies, including immune checkpoint inhibitors and NK cell engagers. We highlight these advancements, discuss current limitations, and propose strategies to optimize NK cell-based therapies for improved cancer treatment outcomes.