ArticleCancer discovery2024
CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis.
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Article in Cancer discovery, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47citing papers in PubMed
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Who cites it
47 citing papers in PubMed.
- Next-generation natural killer cell therapy: bench to bedside and beyond.Signal transduction and targeted therapy · 2026Review
- IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.Molecular therapy. Oncology · 2026Article
- Paracetamol and Metformin Reduce NK-Cell Susceptibility in MCF-7 Breast Cancer Cells in Association with Enrichment of Immune-Evasive CD44International journal of molecular sciences · 2026Article
- CAR-NK cell therapy for hematological malignancies.Blood advances · 2026Review
- Alisertib exerts AURKA-independent antitumor activity in colon cancer by modulating immune-related pathways.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- The search for safe and effective CAR-T targets in AML.Blood cancer journal · 2026Review
- Efficient, fratricide free non-viral engineering of CD70-targeted CAR NK cells for hematologic and solid tumor immunotherapy.Molecular therapy. Advances · 2026Article
- Dual CAR-NK cells targeting PD-L1 and ErbB2 (HER2) exhibit cooperative CAR signaling and counteract solid tumor heterogeneity.Journal of experimental & clinical cancer research : CR · 2026Article
- Constitutive RLI Armoring Enhances CAR-NK Cell Effector Functions but Causes Lethal Toxicity In Vivo.International journal of molecular sciences · 2026Article
- Roads and detours for CAR T cell therapy in autoimmune diseases.Nature reviews. Drug discovery · 2026Review
- CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies.Molecular cancer · 2026Review
- CD70-Targeting CAR NK Cells Overcome BCMA Downregulation and Improve Survival in High-risk Multiple Myeloma Models.Blood cancer discovery · 2026Article
- CD147 regulates CD8iScience · 2026Article
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
- Natural Killer Cell Therapy in Ovarian Cancer: From Preclinical Potentials to Clinical Applications and Combination Strategies.International journal of biological sciences · 2026Review
- Enhancing CAR-NK persistence to unlock its full therapeutic potentials.Frontiers in immunology · 2026Review
- Dual-module aCAR-iCAR NK cells for solid tumors: cascade resistance mechanisms, AI-driven engineering, and precision stratification.Frontiers in immunology · 2026Review
- Harnessing the Power of CAR-NK Cells for Solid Tumors: Challenges, Innovations, and Future Frontiers in Immunotherapy.Cancer communications (London, England) · 2026Review
- Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies.Frontiers in immunology · 2026Review
- Natural killer cell dysfunction in glioma: from immune evasion to immunotherapy.Frontiers in immunology · 2026Review
Corrections and comments
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Authors and funding
47 authors.
Sunil AcharyaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3907-9321
Rafet BasarDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-4713-0454
May DaherDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-6026-8397
Hind RafeiDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5724-4183
Ping LiDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0005-7961-7453
Nadima UpretyDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-4379-6208
Emily EnsleyDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-4212-2260
Mayra ShanleyDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-3739-0287
Bijender KumarDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7835-3875
Pinaki P BanerjeeDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0003-6711-3034
Luciana Melo GarciaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-9148-2193
Paul LinDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-0524-267X
Vakul MohantyDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5536-6750
Kun H KimDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7899-7961
Xianli JiangDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-1697-8575
Yuchen PanDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-1458-1734
Ye LiDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7727-0875
Bin LiuDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0001-3531-9447
Ana K Nunez CortesDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-5380-9274
Chenyu ZhangDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7498-1751
Mohsen FathiWilliam A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas.ORCID 0000-0001-9971-4166
Ali RezvanWilliam A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas.ORCID 0000-0002-1197-0198
Melisa J MontalvoWilliam A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas.ORCID 0009-0008-9395-6998
Sophia L ChaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5344-900X
Francia Reyes-SilvaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0001-5396-7691
Rejeena ShresthaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7642-6735
Xingliang GuoDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0009-6706-7457
Kiran KunduDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7586-4696
Alexander BiederstädtDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-2805-8231
Luis Muniz-FelicianoDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0000-7096-0064
Gary M DeyterDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-2638-0825
Mecit KaplanDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-0079-8617
Xin R JiangDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-8938-8886
Enli LiuDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-4463-7439
Antrix JainMass Spectrometry Proteomics Core, Baylor College of Medicine, Houston, Texas.ORCID 0000-0002-2815-3645
Janos RoszikDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-4561-6170
Natalie W FowlkesDepartment of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-7711-6031
Luisa M Solis SotoDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-1253-630X
Maria G RasoDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-2105-5556
Joseph D KhouryDepartment of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, Omaha, Nebraska.ORCID 0000-0003-2621-3584
Pei LinDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-9844-945X
Francisco VegaDepartment of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-5956-452X
Navin VaradarajanWilliam A. Brookshire Department of Chemical and Biomolecular Engineering, University of Houston, Houston, Texas.ORCID 0000-0001-7524-8228
Ken ChenDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-4013-5279
David MarinDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-0812-9346
Elizabeth J ShpallDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0003-3947-4126
Katayoun RezvaniDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-9599-2246
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8MTumor BiologyP30CA125123 · NCI · BAYLOR COLLEGE OF MEDICINE · PI DAVID R ROWLEY · 2007 to 2026
$73.9MUniversity of Texas M.D. Anderson Cancer SPORE-LeukemiaP50CA100632 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KONOPLEVA, MARINA Y · 2003 to 2023
$43.7MPR1-specific CB T cells for Patients with Myeloid MalignanciesP01CA148600 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KAUR, INDRESHPAL · 2011 to 2022
$24.4MOff-the-shelf engineered NK cells for the treatment of AMLR01CA211044 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI REZVANI, KATY · 2017 to 2021
$2.0MMusIC: A multi-scale technology for integrating dynamic cellular function and molecular profilesR01GM143243 · NIGMS · UNIVERSITY OF HOUSTON · PI VARADARAJAN, NAVIN · 2021 to 2024
$1.8MProstate Cancer Detection Through Urine Headspace Analysis Using Colorimetric SenR43CA180466 · NCI · ISENSE MEDICAL CORPORATION · PI RHODES, PAUL · 2014 to 2014
$150kCancer Prevention and Research Institute of Texas (CPRIT) RP180466National Institutes of Health (NIH) 1 R01CA211044-01National Institutes of Health (NIH) R01GM143243NCI NIH HHS P01 CA148600NCI NIH HHS P30 CA016672NCI NIH HHS P30 CA125123NCI NIH HHS P50 CA100632NCI NIH HHS R01 CA211044NIGMS NIH HHS R01 GM143243Stand Up To Cancer (SU2C) SU2C-AACR-DT-29-19
Abstract
Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.
Indexed as
CD28 AntigensKiller Cells, NaturalReceptors, Chimeric AntigenSignal TransductionAnimalsCD3 ComplexCell Line, TumorHumansImmunotherapy, AdoptiveLymphocyte Specific Protein Tyrosine Kinase p56(lck)MiceXenograft Model Antitumor AssaysCD28 AntigensCD3 ComplexLymphocyte Specific Protein Tyrosine Kinase p56(lck)Receptors, Chimeric Antigen
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