CD73-targeted CAR-NK cell therapy displays potent antitumor activity and translational potential in relapsed/refractory lung adenocarcinoma.
17 affiliations
- 1School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China.
- 2Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China.
- 3Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
- 4Shantou University Medical College, Shantou, Guangdong, 515041, China.
- 5Guangdong Provincial People's Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China.
- 6Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangzhou, Guangdong, 510080, China.
- 7School of Forestry and Biotechnology, Zhejiang A&F University, Hangzhou, China.
- 8National Key Laboratory for Development and Utilization of Forest Food Resources, Zhejiang A&F University, Hangzhou, China.
- 9Shantou University Medical College, Shantou, Guangdong, 515041, China. [email protected].
- 10Guangdong Provincial People's Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China. [email protected].
- 11Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. [email protected].
- 12School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China. [email protected].
- 13Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. [email protected].
- 14Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. [email protected].
- 15School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China. [email protected].
- 16Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. [email protected].
- 17Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. [email protected].
Abstract
Background
Relapsed/refractory (R/R) lung adenocarcinoma (LUAD) remains a clinical challenge with limited therapies and poor prognosis. CAR‑NK cell therapy has shown promise in solid tumors, but its efficacy is limited by both the availability of effective targets and the immunosuppressive tumor microenvironment. CD73 (NT5E), highly expressed across solid tumors, catalyzes adenosine production to drive immunosuppression, representing both a specific CAR‑NK target and a key leverage point to overcome tumor immune evasion. However, its systematic evaluation as a therapeutically actionable target for CAR‑NK cell therapy in R/R LUAD remains unexplored.Methods
We first characterized CD73 expression through integrative analysis of public datasets, primary and relapsed clinical LUAD specimens, and LUAD cell lines derived from primary and metastatic tumors. We then constructed CD73‑CAR‑NK cells and assessed their in vitro cytotoxicity across LUAD cell lines of varying malignancy, as well as their effects on extracellular adenosine and resistance to adenosine‑mediated immunosuppression. Finally, we assessed their antitumor efficacy in a stepwise manner across a tiered panel of in vivo models, including cell line‑derived xenograft (CDX), metastasis, patient‑derived xenograft (PDX), and clinically relevant immune‑humanized PDX models.Results
CD73 expression was elevated in metastasis-derived LUAD cell lines and R/R LUAD specimens. Accordingly, CD73-CAR-NK92 cells exhibited potent cytotoxicity against CD73-high LUAD cells, accompanied by an activated effector phenotype, reduced extracellular adenosine, partial resistance to adenosine-mediated suppression, and limited activity toward normal bronchial epithelial cells. Notably, this enhanced function was consistently observed across multiple NK cell sources including peripheral blood-derived NK (PBNK), umbilical cord blood‑derived NK (UBNK), and iPSC-derived NK (iNK). In vivo, CD73‑CAR‑NK92 cells significantly suppressed tumor growth and metastasis, with enhanced tumor‑site enrichment, prolonged retention, and elevated intratumoral levels of TNF‑α and IFN‑γ. Importantly, in an immune‑humanized PDX mouse model, CD73‑CAR‑NK92 cells significantly reduced the growth of R/R patient‑derived xenografts, accompanied by immune remodeling, without marked systemic inflammation during the observation period.Conclusions
These findings provide preclinical evidence that CD73-CAR-NK cells exhibit potent antitumor efficacy for R/R LUAD through their dual functions of eliminating CD73-high tumor cells and resisting adenosine-mediated immunosuppressive signaling, supporting their therapeutic potential.
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BibTeX
@article{liu2026cd73targeted,
title = {{CD73-targeted CAR-NK cell therapy displays potent antitumor activity and translational potential in relapsed/refractory lung adenocarcinoma.}},
author = {Qianqian Liu and Qifei Dong and Yimei Chen and Nannan Wang and Dian Zhuang and Lihua Chen and Yanzhuo Ye and Shasha Huang and Wenzhao Zhong and Wei Kevin Zhang and Tao Xu and Jiaqi Sun and Huisheng Liu},
journal = {Biomarker research},
year = {2026},
month = oct,
doi = {10.1186/s40364-026-01036-5},
url = {https://europepmc.org/article/MED/42958550},
note = {CC BY},
}
RIS
TY - JOUR
TI - CD73-targeted CAR-NK cell therapy displays potent antitumor activity and translational potential in relapsed/refractory lung adenocarcinoma.
AU - Qianqian Liu
AU - Qifei Dong
AU - Yimei Chen
AU - Nannan Wang
AU - Dian Zhuang
AU - Lihua Chen
AU - Yanzhuo Ye
AU - Shasha Huang
AU - Wenzhao Zhong
AU - Wei Kevin Zhang
AU - Tao Xu
AU - Jiaqi Sun
AU - Huisheng Liu
PY - 2026
DA - 2026/10/28
JO - Biomarker research
DO - 10.1186/s40364-026-01036-5
UR - https://europepmc.org/article/MED/42958550
AB - Background Relapsed/refractory (R/R) lung adenocarcinoma (LUAD) remains a clinical challenge with limited therapies and poor prognosis. CAR‑NK cell therapy has shown promise in solid tumors, but its efficacy is limited by both the availability of effective targets and the immunosuppressive tumor microenvironment. CD73 (NT5E), highly expressed across solid tumors, catalyzes adenosine production to drive immunosuppression, representing both a specific CAR‑NK target and a key leverage point to overcome tumor immune evasion. However, its systematic evaluation as a therapeutically actionable target for CAR‑NK cell therapy in R/R LUAD remains unexplored.Methods We first characterized CD73 expression through integrative analysis of public datasets, primary and relapsed clinical LUAD specimens, and LUAD cell lines derived from primary and metastatic tumors. We then constructed CD73‑CAR‑NK cells and assessed their in vitro cytotoxicity across LUAD cell lines of varying malignancy, as well as their effects on extracellular adenosine and resistance to adenosine‑mediated immunosuppression. Finally, we assessed their antitumor efficacy in a stepwise manner across a tiered panel of in vivo models, including cell line‑derived xenograft (CDX), metastasis, patient‑derived xenograft (PDX), and clinically relevant immune‑humanized PDX models.Results CD73 expression was elevated in metastasis-derived LUAD cell lines and R/R LUAD specimens. Accordingly, CD73-CAR-NK92 cells exhibited potent cytotoxicity against CD73-high LUAD cells, accompanied by an activated effector phenotype, reduced extracellular adenosine, partial resistance to adenosine-mediated suppression, and limited activity toward normal bronchial epithelial cells. Notably, this enhanced function was consistently observed across multiple NK cell sources including peripheral blood-derived NK (PBNK), umbilical cord blood‑derived NK (UBNK), and iPSC-derived NK (iNK). In vivo, CD73‑CAR‑NK92 cells significantly suppressed tumor growth and metastasis, with enhanced tumor‑site enrichment, prolonged retention, and elevated intratumoral levels of TNF‑α and IFN‑γ. Importantly, in an immune‑humanized PDX mouse model, CD73‑CAR‑NK92 cells significantly reduced the growth of R/R patient‑derived xenografts, accompanied by immune remodeling, without marked systemic inflammation during the observation period.Conclusions These findings provide preclinical evidence that CD73-CAR-NK cells exhibit potent antitumor efficacy for R/R LUAD through their dual functions of eliminating CD73-high tumor cells and resisting adenosine-mediated immunosuppressive signaling, supporting their therapeutic potential.
SN - 2050-7771
ER -