Abstract
NK cells are important for the anti-tumour immune response for their potential to kill MHC class I-deficient tumor cells, but they often become dysfunctional in the immune-hostile tumour microenvironment. Here, using single-cell RNA sequencing, we identify an NK cell subpopulation that is specific to triple-negative breast cancers (TNBC) subtype, characterised by the expression of the long non-coding RNA UGDH-AS1. In these NK cells, UGDH-AS1 encodes the micropeptide, NKSM, which renders these NK cells dysfunctional due to the loss of their activation program, which leads to cancer progression. Conditional NKSM knock-in into NK cells of mice results in NK cell deactivation and increased growth of transplanted tumours. Targeted NKSM therapy effectively reduces tumor growth…
Abstract
NK cells are important for the anti-tumour immune response for their potential to kill MHC class I-deficient tumor cells, but they often become dysfunctional in the immune-hostile tumour microenvironment. Here, using single-cell RNA sequencing, we identify an NK cell subpopulation that is specific to triple-negative breast cancers (TNBC) subtype, characterised by the expression of the long non-coding RNA UGDH-AS1. In these NK cells, UGDH-AS1 encodes the micropeptide, NKSM, which renders these NK cells dysfunctional due to the loss of their activation program, which leads to cancer progression. Conditional NKSM knock-in into NK cells of mice results in NK cell deactivation and increased growth of transplanted tumours. Targeted NKSM therapy effectively reduces tumor growth in TNBC mouse models. We find that UGDH-AS1+ NK cells are shaped by the tumor microenvironment (TME). Following upregulation by the TGF-β signaling pathway, NKSM binds to Myc, inhibiting its ERK1/2-mediated phosphorylation at Serine 62 and thus reducing its stability. Decreased Myc activity results in deregulation of T-bet, a key protein involved in NK cell function, which leads to NK cell deactivation. Our study thus provides mechanistic insight int NK cell dysfunctionality in TNBC and lays down the proof of principle for an NK-cell-targeting TNBC immunotherapy.
Data availability
The scRNA-seq count matrix of TNBC tissues was published in Karaayvaz et al.59. The scRNA-seq count matrix of HR+ and HER2+ tissues were published in Liu T et al.60. ChIP-seq data were obtained from the Gene Expression Omnibus (GEO) database:
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104352
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE41580
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51510
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29422
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE61475
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE42958
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE51011
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36354.
The database of IP contaminants was obtained from the Contaminant Repository for Affinity Purification (CRAPome)61. All data supporting the findings described in this manuscript are available in the article and in the Supplementary Information. Source data are provided in this paper.
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Acknowledgements
The work was supported by The National Science Fund for Distinguished Young Scholars (NO. 82125027 to Y.Z.); Jiangsu Provincial Health Commission’s Collaborative Innovation Project in Medical Education, Research, and Industry (NO. YJYC200508 to Y.Z.); The Young Scientists Fund of the National Natural Science Foundation of China(NO. 82303232 to Y.W., and NO. 82303096 to B.G.); National Key R&D Program of China (NO. 2022YFA1305500 to Y.W.); The project funded by China Postdoctoral Science Foundation (NO. 2023T160466 and 2022M722319 to B.G.).
Author contibutions
Y.Z., Z.Z., S.Z., and F.L. designed the experiments, analyzed the data and revised the manuscript. Z.Z., S.Z., and F.L. wrote the manuscript. Z.Z., S.Z., F.L., and X.D. performed most of the experiments. F.L., X.D., and J.D. performed the experiments. Y.W., B.G., W.L., T.Z., S.W., and W.Q.L. contributed to generating and maintaining the cell models. Y.P., S.W., S.Z., W.L., C.J., and H.Z. participated in experiments and analyzed. All of the authors discussed the results and reviewed the manuscript.
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Author notes
These authors contributed equally: Zheng Zhang, Fanrong Li, Xiaoxiao Dai.
Authors and Affiliations
Jiangsu Clinical Medicine Research Institute, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
Zheng Zhang, Shenghua Zhang & Yifeng Zhou 1.
Department of Genetics, Medical College of Soochow University, Suzhou, China
Zheng Zhang, Fanrong Li, Jieqiong Deng, Binbin Guo, Yirong Wang, Wei Liu, Yacheng Pan, Tong Zhao, Shuang Wang, Wanqiu Li, Congnan Jin, Hebin Zhang & Yifeng Zhou 1.
Department of Pathology, The Second Affiliated Hospital of Soochow University, Suzhou, China
Xiaoxiao Dai
Authors
- Zheng Zhang
- Fanrong Li
- Xiaoxiao Dai
- Jieqiong Deng
- Binbin Guo
- Yirong Wang
- Wei Liu
- Yacheng Pan
- Tong Zhao
- Shuang Wang
- Wanqiu Li
- Congnan Jin
- Hebin Zhang
- Shenghua Zhang
- Yifeng Zhou
Corresponding authors
Correspondence to Shenghua Zhang or Yifeng Zhou.
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Cite this article
Zhang, Z., Li, F., Dai, X. et al. The long non-coding RNA UGDH-AS1 encodes an NK-cell-inhibiting micropeptide in triple-negative breast cancers. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66266-x
Received: 11 July 2024
Accepted: 30 October 2025
Published: 12 December 2025
DOI: https://doi.org/10.1038/s41467-025-66266-x