Engineering next-generation CAR-NK cells for hematological malignancies: genome editing, synthetic biology, and precision immunotherapy.
6 affiliations
- 1Faculty of Medicine, Alexandria University, Alexandria, Egypt.
- 2Medical and Pharmaceutical Industrial Biotechnology Department, College of Biotechnology, Misr University for Science and Technology (MUST), Giza, Egypt.
- 3Biology Department, Darb University College, Jazan University, Jazan, Saudi Arabia.
- 4Faculty of Medicine, Cairo University, Kasr AlAiny, Egypt.
- 5Department of Biotechnology and Genetic Engineering, College of Science, Helwan National University, Cairo, Egypt.
- 6Department of Biology, College of Science, Jazan University, Jazan, Saudi Arabia.
Abstract
Chimeric antigen receptor (CAR)-based immunotherapy has transformed cancer treatment by enabling engineered immune cells to selectively recognize and eliminate malignant targets, with CAR-T cells establishing the first major clinical success in this field. However, severe associated toxicities, logistical complexities of autologous manufacturing, and high rates of antigen-loss relapse have accelerated the development of alternative effector platforms such as CAR-NK cells. CAR-NK cells combine antigen-directed cytotoxicity with the innate antitumor functions of natural killer cells, offering a potentially safer and more readily available off-the-shelf therapeutic strategy. Nevertheless, the clinical efficacy of CAR-NK therapy is constrained by key biological and translational hurdles: brief in vivo persistence, inadequate trafficking and solid tumor infiltration, severe susceptibility to tumor microenvironment-mediated immunosuppression, and antigen escape driven by tumor heterogeneity. These biological constraints are compounded by technical bottlenecks, including cell source variability, limited large-scale expansion capacity, ex vivo functional exhaustion, and an absence of standardized manufacturing protocols. To address these multi-faceted barriers, recent advances in genome engineering, systems biology, and computational modeling provide promising routes forward. Given that prolonged exposure to immunosuppressive niches induces functional impairment, genome-editing strategies targeting inhibitory checkpoints and persistence programs are crucial; however, enhancing persistence requires stringent safeguards to mitigate toxicity risks from constitutive signaling or genomic instability. Thus, engineering next-generation CAR-NK cells necessitates balancing extended longevity, potent cytotoxicity, and safety. Multiomics approaches facilitate deeper characterization of CAR-NK functional states and tumor-immune interactions, whereas artificial intelligence-guided engineering integrates high-dimensional biological and manufacturing data to optimize receptor design, predict therapeutic performance, and accelerate translational workflows. Collectively, these innovations support a paradigm shift toward programmable CAR-NK cells that can dynamically sense, adapt, and respond to tumor evolution, driving the transition toward autonomous, highly scalable, and precisely controllable cellular immunotherapies in precision oncology.
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BibTeX
@article{bahr2026engineering,
title = {{Engineering next-generation CAR-NK cells for hematological malignancies: genome editing, synthetic biology, and precision immunotherapy.}},
author = {Ahmed Reda Bahr and Youssef Basem and Amani Alhejely and Abdel Rahman Alaa and Saifallah Mabrouk Abozeid and Amira Basem and Mohsen A Khormi and Mabrouk A Abo-Zaid},
journal = {Frontiers in genome editing},
year = {2026},
month = oct,
doi = {10.3389/fgeed.2026.1943068},
url = {https://europepmc.org/article/MED/42947991},
note = {CC BY},
}
RIS
TY - JOUR
TI - Engineering next-generation CAR-NK cells for hematological malignancies: genome editing, synthetic biology, and precision immunotherapy.
AU - Ahmed Reda Bahr
AU - Youssef Basem
AU - Amani Alhejely
AU - Abdel Rahman Alaa
AU - Saifallah Mabrouk Abozeid
AU - Amira Basem
AU - Mohsen A Khormi
AU - Mabrouk A Abo-Zaid
PY - 2026
DA - 2026/10/13
JO - Frontiers in genome editing
DO - 10.3389/fgeed.2026.1943068
UR - https://europepmc.org/article/MED/42947991
AB - Chimeric antigen receptor (CAR)-based immunotherapy has transformed cancer treatment by enabling engineered immune cells to selectively recognize and eliminate malignant targets, with CAR-T cells establishing the first major clinical success in this field. However, severe associated toxicities, logistical complexities of autologous manufacturing, and high rates of antigen-loss relapse have accelerated the development of alternative effector platforms such as CAR-NK cells. CAR-NK cells combine antigen-directed cytotoxicity with the innate antitumor functions of natural killer cells, offering a potentially safer and more readily available off-the-shelf therapeutic strategy. Nevertheless, the clinical efficacy of CAR-NK therapy is constrained by key biological and translational hurdles: brief in vivo persistence, inadequate trafficking and solid tumor infiltration, severe susceptibility to tumor microenvironment-mediated immunosuppression, and antigen escape driven by tumor heterogeneity. These biological constraints are compounded by technical bottlenecks, including cell source variability, limited large-scale expansion capacity, ex vivo functional exhaustion, and an absence of standardized manufacturing protocols. To address these multi-faceted barriers, recent advances in genome engineering, systems biology, and computational modeling provide promising routes forward. Given that prolonged exposure to immunosuppressive niches induces functional impairment, genome-editing strategies targeting inhibitory checkpoints and persistence programs are crucial; however, enhancing persistence requires stringent safeguards to mitigate toxicity risks from constitutive signaling or genomic instability. Thus, engineering next-generation CAR-NK cells necessitates balancing extended longevity, potent cytotoxicity, and safety. Multiomics approaches facilitate deeper characterization of CAR-NK functional states and tumor-immune interactions, whereas artificial intelligence-guided engineering integrates high-dimensional biological and manufacturing data to optimize receptor design, predict therapeutic performance, and accelerate translational workflows. Collectively, these innovations support a paradigm shift toward programmable CAR-NK cells that can dynamically sense, adapt, and respond to tumor evolution, driving the transition toward autonomous, highly scalable, and precisely controllable cellular immunotherapies in precision oncology.
SN - 2673-3439
ER -