Harnessing the Power of NK Cell Receptor Engineering as a New Prospect in Cancer Immunotherapy

Natural killer (NK) cells have recently gained popularity as an alternative for cancer immunotherapy. Adoptive cell transfer employing NK cells offers a safer therapeutic option compared to T-cell-based therapies, due to their significantly lower toxicity and the availability of diverse autologous and allogeneic NK cell sources. However, several challenges are associated with NK cell therapies, including limited in vivo persistence, the immunosuppressive and hostile tumor microenvironment (TME), and the lack of effective treatments for solid tumors. To address these limitations, the modification of NK cells to stably produce cytokines has been proposed as a strategy to enhance their persistence and proliferation. Additionally, the overexpression of activating receptors and the blockade of inhibitory receptors can restore the NK cell functions hindered by the TME. To further improve tumor infiltration and the elimination of solid tumors, innovative approaches focusing on the enhancement of NK cell chemotaxis through the overexpression of chemotactic receptors have been introduced. This review highlights the latest advancements in preclinical and clinical studies investigating the engineering of activating, inhibitory, and chemotactic NK cell receptors; discusses recent progress in cytokine manipulation; and explores the potential of combining the chimeric antigen receptor (CAR) technology with NK cell receptors engineering.