NK cell receptors in anti-tumor and healthy tissue protection: Mechanisms and therapeutic advances

• NK cells are innate immune cells whose activity is tightly regulated by the integration of inhibitory and activating receptor signals. • NK cells are cytotoxic lymphocytes that, due to their molecular arsenal, play a pivotal role in cancer immunosurveillance. • The tumor microenvironment employs various escape mechanisms that undermine NK cell function and limit the efficacy of NK cell-based immunotherapy in solid tumors. • NK cells based immunotherapeutic approaches represent more than promising tools in restoring NK cell activity, achieving an effective treatment against cancers. Natural Killer (NK) cells are integral to the innate immune system, renowned for their ability to target and eliminate cancer cells without the need for antigen presentation, sparing normal tissues. These cells are crucial in cancer immunosurveillance due to their diverse array of activating and inhibitory receptors that modulate their cytotoxic activity. However, the tumor microenvironment can suppress NK cell function through various mechanisms. Over recent decades, research has focused on overcoming these tumor escape mechanisms. Initially, efforts concentrated on enhancing T cell activity, leading to impressive results with immunotherapeutic approaches aimed at boosting T cell responses. Nevertheless, a substantial number of patients do not benefit from these treatments and continue to seek effective alternatives. In this context, NK cells present a promising avenue for developing new treatments, given their potent cytotoxic capabilities, safety profile, and activity against T cell-resistant tumors, such as those lacking HLA-I expression. Recent advancements in immunotherapy include strategies to restore and amplify NK cell activity through immune checkpoint inhibitors, cytokines, adoptive NK cell therapy, and CAR-NK cell technology. This review provides a comprehensive overview of NK cell receptors, the tumor escape mechanisms that hinder NK cell function, and the evolving field of NK cell-based cancer immunotherapy, highlighting ongoing efforts to develop more effective and targeted cancer treatment strategies.