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©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
Natural killer cell-based immunotherapies for colorectal cancer: Current strategies, challenges, and future perspectives
Xiao-Jun Zhang, Yan Yu, Jing-Yu Li, Yu-Zhu Yan, Sha-Sha Jiang, Yi Zhang, Qin Fei, Yi-Ran Zhang, Yong-Xin Zhao, Lei Guo, Jing Lv, He-Ping Zhao
Xiao-Jun Zhang, Yan Yu, Yu-Zhu Yan, Sha-Sha Jiang, Yi Zhang, Yi-Ran Zhang, Yong-Xin Zhao, Jing Lv, He-Ping Zhao, Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
Jing-Yu Li, Highway College, Chang’an University, Xi’an 710054, Shaanxi Province, China
Qin Fei, Department of Anesthesiology, The Third People’s Hospital of Chengdu, Chengdu 610031, Sichuan Province, China
Lei Guo, Department of Spine Surgery, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
Co-first authors: Xiao-Jun Zhang and Yan Yu.
Co-corresponding authors: Jing Lv and He-Ping Zhao.
Author contributions: Zhang XJ and Yu Y contributed equally to this work and are co-first authors of the manuscript; Lv J and Zhao HP contributed equally to this work and are co-corresponding authors of the manuscript. Zhang XJ and Lv J searched and reviewed published articles, wrote and revised the manuscript, and made substantial contributions to the conception and design of this study; Zhang XJ, Yu Y, Li JY, Yan YZ, Jiang SS, Zhang Y, Fei Q, Zhang YR, Zhao YX, Guo L, Lv J, and Zhao HP critically reviewed and revised the manuscript; and all authors have read and approved the final manuscript.
Supported by Shaanxi Natural Science Foundation of China, No. 2025JC-YBMS-916; and Xi’an Municipal Health Commission of China, No. 2023ms11.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Jing Lv, MD, Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, No. 555 Youyi East Road, Xi’an 710054, Shaanxi Province, China.
lvjing-1219@163.com
Received: May 28, 2025
Revised: June 21, 2025
Accepted: August 18, 2025
Published online: September 14, 2025
Processing time: 100 Days and 4.1 Hours
Natural killer (NK) cells have emerged as promising therapeutic agents for treating colorectal cancer because of their innate ability to recognize and eliminate tumor cells without prior sensitization. In this review, NK cell-based immunotherapeutic approaches, including cytokine therapy, immune checkpoint inhibition, antibody-dependent cellular cytotoxicity, and adoptive cell transfer, are comprehensively examined, and their respective clinical potential and limitations are highlighted. We discuss critical challenges in NK cell expansion, genetic engineering (particularly chimeric antigen receptor-NK development), and tumor microenvironment-mediated immunosuppression. Furthermore, we explore innovative strategies such as combination therapies, nanotechnology-enhanced delivery, and personalized medicine approaches that aim to overcome the current barriers. The review concludes with future directions emphasizing the need for standardized manufacturing protocols, new strategies to improve NK cell persistence, and clinical validation of emerging technologies, positioning NK cell immunotherapy as a transformative modality for colorectal cancer treatment.
Core Tip: Natural killer (NK) cell-based immunotherapy represents a breakthrough approach for treating colorectal cancer (CRC), particularly for microsatellite-stable tumors resistant to conventional treatments. Currently employed strategies, including cytokine therapy, checkpoint inhibition, and chimeric antigen receptor-NK cell therapy, show promise in CRC treatment, but manufacturing challenges and the immunosuppressive tumor microenvironment limit their efficacy. Emerging solutions combining gene-editing, nanotechnology, and personalized approaches may overcome these barriers, positioning NK cell therapy as a transformative CRC treatment modality.
