CAR-NK cell immunotherapy: a comprehensive review of engineering platforms, clinical applications in hematological and solid tumors.
6 affiliations
- 1Faculty of Medicine, Benha National University, Obour, Egypt.
- 2Faculty of Medicine, Benha National University, Obour, Egypt. [email protected].
- 3Faculty of Medicine, Alexandria University, Alexandria, Egypt.
- 4Faculty of Medicine, Tanta University, Tanta, Egypt.
- 5Allama Iqbal Medical College, Lahore, Pakistan.
- 6Assistant Professor of Surgery, Director of Breast Surgical Services, Texas Tech University Health Sciences Center, El Paso, USA.
Abstract
Chimeric antigen receptor-natural killer (CAR-NK) cells combine innate cytotoxicity with antigen-directed killing and promise as an immunotherapy with lower cytokine toxicity than CAR-T approaches. However, clinical translation is limited by challenges in transduction, persistence, tumor infiltration, and the immunosuppressive tumor microenvironment (TME). We performed a comprehensive literature review of recent preclinical and early-phase clinical studies, engineering strategies (CAR design, transduction technologies, gene-editing), manufacturing and expansion protocols, and trial outcomes in this review. We noted a reference to the advantages of CAR-NK, like multimodal killing (CAR-dependent and innate pathways), potential for allogeneic "off-the-shelf" use, and favorable early safety profiles. However, NK-specific obstacles persist: lower viral transduction efficiencies, short in vivo persistence, poor infiltration into solid tumors, and TME-mediated suppression (TGF-β, adenosine, metabolic stress). Engineering countermeasures such as IL-15 expression, checkpoint receptor knockout, chemokine receptor co-expression (e.g., CXCR1/4), DAP10/DAP12-based signaling domains, and non-viral delivery (transposons/CRISPR) have shown preclinical promise. CAR-NK therapy has developed from concept to a clinically actionable treatment line for hematologic malignancies and shows emerging potential in solid tumors when combined with TME-modulating strategies. This review provides robust evidence about CAR-NK therapies in hematological and solid tumors, with a great emphasis on the challenges they encounter, strategies, and innovative approaches to overcome these challenges, and forward-looking perspectives to improve future therapeutic CAR-NK designs and clinical outcomes.
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BibTeX
@article{awadallah2026carnk,
title = {{CAR-NK cell immunotherapy: a comprehensive review of engineering platforms, clinical applications in hematological and solid tumors.}},
author = {Salma Mohamed Awadallah and NourEldin Elmesalamy and Ahmed Reda Bahr and Basant Atef and Eeman Afroz and Hank C Hill},
journal = {Journal of cancer research and clinical oncology},
year = {2026},
month = oct,
doi = {10.1007/s00432-026-06635-1},
url = {https://europepmc.org/article/MED/42926223},
note = {CC BY},
}
RIS
TY - JOUR
TI - CAR-NK cell immunotherapy: a comprehensive review of engineering platforms, clinical applications in hematological and solid tumors.
AU - Salma Mohamed Awadallah
AU - NourEldin Elmesalamy
AU - Ahmed Reda Bahr
AU - Basant Atef
AU - Eeman Afroz
AU - Hank C Hill
PY - 2026
DA - 2026/10/23
JO - Journal of cancer research and clinical oncology
DO - 10.1007/s00432-026-06635-1
UR - https://europepmc.org/article/MED/42926223
AB - Chimeric antigen receptor-natural killer (CAR-NK) cells combine innate cytotoxicity with antigen-directed killing and promise as an immunotherapy with lower cytokine toxicity than CAR-T approaches. However, clinical translation is limited by challenges in transduction, persistence, tumor infiltration, and the immunosuppressive tumor microenvironment (TME). We performed a comprehensive literature review of recent preclinical and early-phase clinical studies, engineering strategies (CAR design, transduction technologies, gene-editing), manufacturing and expansion protocols, and trial outcomes in this review. We noted a reference to the advantages of CAR-NK, like multimodal killing (CAR-dependent and innate pathways), potential for allogeneic "off-the-shelf" use, and favorable early safety profiles. However, NK-specific obstacles persist: lower viral transduction efficiencies, short in vivo persistence, poor infiltration into solid tumors, and TME-mediated suppression (TGF-β, adenosine, metabolic stress). Engineering countermeasures such as IL-15 expression, checkpoint receptor knockout, chemokine receptor co-expression (e.g., CXCR1/4), DAP10/DAP12-based signaling domains, and non-viral delivery (transposons/CRISPR) have shown preclinical promise. CAR-NK therapy has developed from concept to a clinically actionable treatment line for hematologic malignancies and shows emerging potential in solid tumors when combined with TME-modulating strategies. This review provides robust evidence about CAR-NK therapies in hematological and solid tumors, with a great emphasis on the challenges they encounter, strategies, and innovative approaches to overcome these challenges, and forward-looking perspectives to improve future therapeutic CAR-NK designs and clinical outcomes.
SN - 0171-5216
SN - 1432-1335
ER -