{ "abstract": "Background\n\nRelapsed/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\n\nWe 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\n\nCD73 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\n\nThese 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.", "abstract_shown": true, "affiliations": [ "School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China.", "Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China.", "Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.", "Shantou University Medical College, Shantou, Guangdong, 515041, China.", "Guangdong Provincial People's Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China.", "Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangzhou, Guangdong, 510080, China.", "School of Forestry and Biotechnology, Zhejiang A&F University, Hangzhou, China.", "National Key Laboratory for Development and Utilization of Forest Food Resources, Zhejiang A&F University, Hangzhou, China.", "Shantou University Medical College, Shantou, Guangdong, 515041, China. syzhongwenzhao@scut.edu.cn.", "Guangdong Provincial People's Hospital, Guangdong Lung Cancer Institute, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510080, China. syzhongwenzhao@scut.edu.cn.", "Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. zhang_wei@gzlab.ac.cn.", "School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China. xu_tao@gzlab.ac.cn.", "Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. xu_tao@gzlab.ac.cn.", "Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. sun_jiaqi@gzlab.ac.cn.", "School of Biomedical Engineering, Guangzhou Medical University, Guangzhou, Guangdong, 511495, China. liu_huisheng@gzlab.ac.cn.", "Guangzhou National Laboratory, Guangzhou, Guangdong, 510320, China. liu_huisheng@gzlab.ac.cn.", "Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. liu_huisheng@gzlab.ac.cn." ], "article_type": "research article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0, 1 ], "name": "Qianqian Liu" }, { "affs": [ 1, 2 ], "name": "Qifei Dong" }, { "affs": [ 3, 4, 5 ], "name": "Yimei Chen" }, { "affs": [ 1 ], "name": "Nannan Wang" }, { "affs": [ 0, 1 ], "name": "Dian Zhuang" }, { "affs": [ 6, 7 ], "name": "Lihua Chen" }, { "affs": [ 0, 1 ], "name": "Yanzhuo Ye" }, { "affs": [ 1 ], "name": "Shasha Huang" }, { "affs": [ 8, 9 ], "name": "Wenzhao Zhong" }, { "affs": [ 10 ], "name": "Wei Kevin Zhang" }, { "affs": [ 11, 12 ], "name": "Tao Xu" }, { "affs": [ 13 ], "name": "Jiaqi Sun" }, { "affs": [ 14, 15, 16 ], "name": "Huisheng Liu" } ], "bibtex": "https://research.draconitic.com/paper/5dx51ccmf6zxx.bib", "cited_by": 0, "doi": "10.1186/s40364-026-01036-5", "fulltext_url": "https://europepmc.org/articles/PMC13718019", "id": "5dx51ccmf6zxx", "issns": [ "2050-7771" ], "landing_url": "https://europepmc.org/article/MED/42958550", "language": "eng", "licence": "CC-BY", "licence_label": "CC BY", "licence_source": "article", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "heading", "Research" ], [ "openalex", "2730|CAR-T cell therapy research" ] ], "openalex": "W7224659846", "pdf_url": "https://europepmc.org/articles/PMC13718019?pdf=render", "pmcid": "PMC13718019", "pmid": "42958550", "published": "2026-10-28", "publisher": "BMC", "ris": "https://research.draconitic.com/paper/5dx51ccmf6zxx.ris", "sources": [ { "first_seen": "2026-11-01T00:20:36Z", "native_id": "MED:42958550", "source": "europepmc", "url": "https://europepmc.org/article/MED/42958550" }, { "first_seen": "2026-11-02T12:22:11Z", "native_id": "PMC13718019", "source": "pmc", "url": "https://doi.org/10.1186/s40364-026-01036-5" } ], "subjects": [ { "field": "medicine", "origin": "openalex:2730|CAR-T cell therapy research", "subfield": "oncology" } ], "title": "CD73-targeted CAR-NK cell therapy displays potent antitumor activity and translational potential in relapsed/refractory lung adenocarcinoma.", "title_text": "CD73-targeted CAR-NK cell therapy displays potent antitumor activity and translational potential in relapsed/refractory lung adenocarcinoma.", "type": "peer-reviewed", "updated_at": "2026-11-02T12:22:11Z", "url": "https://research.draconitic.com/paper/5dx51ccmf6zxx", "venue": "Biomarker research", "versions": [] }