Fighting Cancer Metastasis by Natural Killer Cells: Mechanistic Insights and Therapeutic Innovations Publisher



Yarahmadi M ; Alavimoghadam S ; Bahramivahdat E ; Keshtkari S ; Karimi M ; Namazi N ; Rezaeitavirani M ; Hojjatassari S ; Jahangiri M ; Nejatiniyaki SM ; Arjmand B
Source: Regenerative Engineering and Translational Medicine Published:2025

Abstract

Purpose: Metastasis is one of the critical problems in cancer treatment and ranks among the top in tumor-related mortality. When a tumor has metastasized to other organs, therapy against such a tumor is problematic. Herein, the authors aimed to give insight into the importance of NK cells in controlling metastasis by discussing their molecular mechanisms and presenting recent research involving NK cell–based strategies in metastatic cancer treatment along with distilling main challenges, opportunities, and future directions for optimizing clinical outcomes. Methods: A literature review was conducted based on Google Scholar, PubMed, and Web of Science searching on the recent studies and advances in the field of molecular mechanisms underlying NK cell–mediated cytotoxicity and recent innovations, especially chimeric antigen receptor-NK therapies. Results: NK cells with cytotoxic effects are the first line of defense against tumor cells. NK cells can diminish cancer cells by secreting granzymes and perforin or increasing apoptosis by TNFa, FasL, and TRAIL. NK cells effectively lyse circulating tumor cells via the formation of an immune synapse, polarization of cytotoxic granules, and release of toxic molecules. Additionally, NK cells can lead to apoptosis of metastatic tumor cells by activating the DNAM-1 and ERK pathways. Thus, NK cells have a potential role in protection against cancer metastases. New methods are now being used or investigated to overcome cancer metastasis. Although each of those therapies has some limitations, CAR-NK therapies appear promising, with limited toxicities compared to standard treatments. Conclusion: The future of enhanced NK cell recruitment, activation, and persistence within tumors may provide options for the treatment of metastatic cancer. Understanding the molecular processes of NK cell activity is vital for optimizing immunotherapy strategies. Lay Summary. Most cancer deaths are due to the spread of cancer called metastasis. Key players in immunity, natural killer cells target and prevent the spread of circulating tumor cells. They eliminate tumor cells in three steps: formation of an immune synapse, reorientation of toxic granules, and their release. Recent advances using chimeric antigen receptor-NK cell therapy have been promising, with fewer side effects. Research in enhancing NK cell activation and persistence in the tumor is essential for the development of better treatments emphasizing their role in advancing cancer immunotherapy. © 2025 Elsevier B.V., All rights reserved.