Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 0 0 2026 04 16 1 35 EN Asieh Emami Nejad Department of Biology, Payame Noor University, Tehran, Iran Saham Shaverdi Department of Biology, Payame Noor University, Tehran, Iran Marjan Taherian Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran Azim Forouzan Department of Gastroenterology and Hepatology, Clinical Research Development Unit, Amiralmomnin Hospital, School of Medicine, Arak University of Medical Sciences ,Arak, Iran Ali Sadoogh Abbasian Department of Nephrology, Clinical Research Development Unit of Amiralmomnin Hospital, School of Medicine, Arak University of Medical Sciences ,Arak, Iran Mohammadreza Rohani Department of Gastroenterology and Hepatology Internal Medicine, School of Medicine, Saveh University of Medical Sciences, Saveh, Iran Mojtaba Ahmadlou Department of Biostatistics, Clinical Research Development Unit of Amiralmomnin Hospital, School of Medicine, Arak University of Medical Sciences ,Arak, Iran Sayed Mohammad Matin Ishaghi Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran Elnaz Sheydaee Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran Simin Najafgholian Department of Emergency Medicine, Clinical Research Development Unit, Valiasr Hospital, Arak University of Medical Science, Arak, Iran Mostafa Manian Department of Medical Laboratory Science, KerMS.C., Islamic Azad University, Kermanshah, Iran 2025 08 20 2025 12 01 Chimeric antigen receptor–natural killer (CAR-NK) cell therapy holds significant promise for cancer immunotherapy due to its efficient recognition and lysis of malignant cells. Despite the potential of CAR-NK therapy as a safer and more effective immunotherapeutic strategy, researchers are actively focusing on addressing its limitations. These include enhancing persistence, optimizing genetic engineering methods, and standardizing the production process for wider clinical applicability. The development of novel generations of CAR-NK cells, combined with a deeper understanding of their behavior in solid tumors, could potentially revolutionize cancer cell therapy and improve patient outcomes in the near future. However, to improve clinical outcomes and facilitate the broader application of CAR-NK cell therapies, we must address challenges related to the optimization of CAR constructs, in vivo persistence, tumor penetration, safety, and regulatory considerations. Overall, the article presents an extensive review of the challenges and potential strategies for improving the long-term antitumor efficacy of CAR-NK cell therapy, emphasizing the importance of combination therapies, drug delivery methods, and immune checkpoint blockade in enhancing the effectiveness of NK cell–based immunotherapy. The paper provides valuable insights into the intricate mechanisms and potential future applications of these strategies in cancer immunotherapy. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4558 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4558/2324