CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy
Abstract Chimeric antigen receptor (CAR)-NK therapy holds great potential for tumor treatment, but current CAR designs are primarily optimized for T cells, raising concerns about their suitability for NK cells. This study compared two dominant CAR designs used in T cells—CD28-CD3ζ (28z) and 4-1BB-CD...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
|
| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-025-00618-7 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850029890305261568 |
|---|---|
| author | Pengchao Zhang Xuejia Feng Xiangyun Niu Zhongming Liu Minghui Li Maoxuan Liu Dehong Yan Guizhong Zhang Xiaochun Wan |
| author_facet | Pengchao Zhang Xuejia Feng Xiangyun Niu Zhongming Liu Minghui Li Maoxuan Liu Dehong Yan Guizhong Zhang Xiaochun Wan |
| author_sort | Pengchao Zhang |
| collection | DOAJ |
| description | Abstract Chimeric antigen receptor (CAR)-NK therapy holds great potential for tumor treatment, but current CAR designs are primarily optimized for T cells, raising concerns about their suitability for NK cells. This study compared two dominant CAR designs used in T cells—CD28-CD3ζ (28z) and 4-1BB-CD3ζ (BBz)—and found that CD28 costimulation offers superior functionality in NK cells. 28z CAR-NK cells exhibited significantly better activation, cytotoxicity, and in vivo anti-tumor efficacy than BBz CAR-NK cells, with similar persistence and tumor infiltration. 28z CAR more effectively recruited the ZAP70 kinase and upregulated multiple key factors involved in immune activation, potentially augmenting CAR-NK cell function. MAP3K8, a kinase involved in inflammation and the MAPK signaling pathway, was identified as a critical mediator in enhancing 28z CAR-NK cell function. Silencing or inhibiting MAP3K8 impaired the anti-tumor activity of 28z CAR-NK cells, while its overexpression substantially improved the function of BBz CAR-NK cells. These findings provide new insights into how CD28 costimulation boosts CAR-NK cell efficacy, supporting its use into NK cell-specific CARs for cancer immunotherapy, and highlight MAP3K8 as a potential target for optimizing BBz CAR-NK cell therapy. |
| format | Article |
| id | doaj-art-d6ee4d307e544088b58c0e9a9cec8e82 |
| institution | DOAJ |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-d6ee4d307e544088b58c0e9a9cec8e822025-08-20T02:59:23ZengBMCExperimental Hematology & Oncology2162-36192025-03-011411510.1186/s40164-025-00618-7CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapyPengchao Zhang0Xuejia Feng1Xiangyun Niu2Zhongming Liu3Minghui Li4Maoxuan Liu5Dehong Yan6Guizhong Zhang7Xiaochun Wan8Center for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesCenter for Protein and Cell-based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of SciencesAbstract Chimeric antigen receptor (CAR)-NK therapy holds great potential for tumor treatment, but current CAR designs are primarily optimized for T cells, raising concerns about their suitability for NK cells. This study compared two dominant CAR designs used in T cells—CD28-CD3ζ (28z) and 4-1BB-CD3ζ (BBz)—and found that CD28 costimulation offers superior functionality in NK cells. 28z CAR-NK cells exhibited significantly better activation, cytotoxicity, and in vivo anti-tumor efficacy than BBz CAR-NK cells, with similar persistence and tumor infiltration. 28z CAR more effectively recruited the ZAP70 kinase and upregulated multiple key factors involved in immune activation, potentially augmenting CAR-NK cell function. MAP3K8, a kinase involved in inflammation and the MAPK signaling pathway, was identified as a critical mediator in enhancing 28z CAR-NK cell function. Silencing or inhibiting MAP3K8 impaired the anti-tumor activity of 28z CAR-NK cells, while its overexpression substantially improved the function of BBz CAR-NK cells. These findings provide new insights into how CD28 costimulation boosts CAR-NK cell efficacy, supporting its use into NK cell-specific CARs for cancer immunotherapy, and highlight MAP3K8 as a potential target for optimizing BBz CAR-NK cell therapy.https://doi.org/10.1186/s40164-025-00618-7CAR-NKTranscriptomicsCD284-1BBMAP3K8 |
| spellingShingle | Pengchao Zhang Xuejia Feng Xiangyun Niu Zhongming Liu Minghui Li Maoxuan Liu Dehong Yan Guizhong Zhang Xiaochun Wan CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy Experimental Hematology & Oncology CAR-NK Transcriptomics CD28 4-1BB MAP3K8 |
| title | CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy |
| title_full | CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy |
| title_fullStr | CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy |
| title_full_unstemmed | CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy |
| title_short | CD28 is superior to 4-1BB costimulation in generating CAR-NK cells for tumor immunotherapy |
| title_sort | cd28 is superior to 4 1bb costimulation in generating car nk cells for tumor immunotherapy |
| topic | CAR-NK Transcriptomics CD28 4-1BB MAP3K8 |
| url | https://doi.org/10.1186/s40164-025-00618-7 |
| work_keys_str_mv | AT pengchaozhang cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT xuejiafeng cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT xiangyunniu cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT zhongmingliu cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT minghuili cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT maoxuanliu cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT dehongyan cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT guizhongzhang cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy AT xiaochunwan cd28issuperiorto41bbcostimulationingeneratingcarnkcellsfortumorimmunotherapy |