Cell-based immunotherapies have transformed cancer treatment, yet their widespread use remains constrained by safety risks, manufacturing complexity, and limited effectiveness against solid tumors. CAR-T cell therapy, while highly effective in certain blood cancers, is frequently associated with cytokine release syndrome, neurotoxicity, and prolonged production timelines. These challenges highlight the need for alternative immune cell platforms that retain antitumor potency while reducing clinical risk. Natural killer cells possess inherent cytotoxicity, do not require antigen presentation through major histocompatibility complexes, and rarely cause graft-versus-host disease. Based on these challenges, there is a growing need to explore CAR-NK cell therapy as a safer and more adaptable immunotherapeutic strategy.
In a review published (DOI: 10.1007/s12519-025-00998-0) in World Journal of Pediatrics in November 2025, researchers from Children’s Hospital, Zhejiang University School of Medicine, together with collaborators from multiple medical and research institutions across China, comprehensively summarize recent advances in CAR-NK cell therapy. The review examines progress in CAR design, natural killer cell sourcing, expansion technologies, and gene-transfer strategies, while also assessing emerging preclinical and clinical evidence. The authors highlight how CAR-NK cells may offer safer, scalable, and more accessible alternatives to existing CAR-T therapies, particularly in cancer and immune-related diseases.
The review describes CAR-NK cells as engineered immune effectors that integrate synthetic antigen-recognition receptors with the natural cytotoxic mechanisms of NK cells. Compared with T cells, NK cells can eliminate target cells through multiple pathways, including perforin-granzyme release and death-receptor signaling, while also retaining the ability to kill antigen-negative tumor variants. This dual targeting capacity may reduce tumor escape, a common cause of relapse.
Technological innovations have significantly improved CAR-NK performance. Optimized CAR structures tailored to NK-specific signaling pathways enhance activation strength and persistence. Diverse cell sources—including peripheral blood, umbilical cord blood, and induced pluripotent stem cells—enable large-scale production and cryopreservation, supporting off-the-shelf treatment models. Advances in viral and non-viral gene-transfer methods further increase manufacturing flexibility and safety.
Clinically, CAR-NK cells have demonstrated encouraging safety profiles and preliminary efficacy in hematological malignancies, with minimal reports of cytokine release syndrome or neurotoxicity. Emerging data also suggest potential applications in solid tumors and autoimmune diseases, although challenges remain in maintaining in-vivo persistence and overcoming immunosuppressive tumor microenvironments. Collectively, these developments position CAR-NK therapy as a rapidly evolving immunotherapeutic platform.
“CAR-NK cell therapy represents a strategic shift in immune engineering,” the authors note. “By leveraging the intrinsic biology of natural killer cells, this approach offers the possibility of safer, readily available cellular therapies without compromising antitumor activity.” The review emphasizes that continued optimization of CAR design, combination therapies, and personalized strategies will be essential to maximize therapeutic benefit. According to the authors, CAR-NK cells are not only a treatment modality but also a powerful tool for understanding immune regulation and advancing precision medicine.
If successfully translated at scale, CAR-NK cell therapy could significantly broaden patient access to advanced immunotherapies. Off-the-shelf production models may reduce costs, shorten treatment timelines, and enable rapid intervention for patients with aggressive or treatment-resistant diseases. Beyond oncology, the selective targeting capabilities of CAR-NK cells open new possibilities for managing autoimmune disorders and infectious diseases with greater precision and fewer side effects. As engineering strategies continue to evolve, CAR-NK cells are poised to become a central pillar of next-generation immunotherapy and a key driver of safer, more personalized medical treatments.
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References
DOI
10.1007/s12519-025-00998-0
Original Source URL
https://doi.org/10.1007/s12519-025-00998-0
Funding Information
This work was supported by the Central Government Guiding Local Science and Technology Development Fund of Zhejiang Province (grant/award number: 2024ZY01007), the Key Research and Development Program of Zhejiang Province (grant/award number: 2025C02079), the Construction Fund of Key Medical Disciplines of Hangzhou, Laboratory Diagnostics (grant/award number: 2025HZZD01) and the Zhejiang Provincial Medical and Health Project, Traditional Chinese Medicine Research Program (grant/award number: 2024037550).
About World Journal of Pediatrics
World Journal of Pediatrics is a monthly, peer-reviewed academic journal that publishes original research articles, reviews, and special reports covering all aspects of pediatrics. It welcomes contributions from pediatricians and researchers worldwide, focusing on the latest developments in pediatric clinical practice, pediatric surgery, preventive child healthcare, pharmacology, stomatology, and biomedicine, as well as basic and experimental sciences. The journal provides an international platform for academic exchange and dissemination of medical research findings. The 2024 journal impact factor is 4.5 (Q1 in the category of PEDIATRICS). All submissions undergo rigorous peer review by at least two experts. Committed to efficient manuscript processing, the journal aims to deliver final decisions within two months, with outstanding papers or special reports potentially accepted within one month for priority publication.