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Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma

Oncogene (2025)Cite this article

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Abstract

Derlin-3 has been implicated as an essential element in the degradation of misfolded lumenal glycoproteins induced by endoplasmic reticulum (ER) stress. However, its potential biomechanisms in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) remains to be elucidated. In the present study, we found that Derlin-3 was predominantly elevated in LUAD tissues, and could predict worse prognosis of LUAD patients. ScRNA-seq analysis indicated that Derlin-3 was mainly enriched in B lymphocytes in the TME, especially in plasma cells. Moreover, Derlin-3 may be involved in ER stress and IgG4 secretion in plasma cells by targeting Hrd1/p38/PRDM1 pathway. While the aberrant IgG4 production may be an essential driver of the polarization of macrophages towards the M2 phenotype. Additionally, downregulation of Derlin-3 could inhibit plasma cells infiltration and M2 macrophage polarization in vivo. Our results indicated that Derlin-3 could shape TME via ER stress to harness immune function, which might serve as a promising immunotherapeutic target in LUAD.

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Fig. 1: Expression of Derlin-3 in LUAD was associated with worse prognosis.
Fig. 2: Summary of the clustering and annotation of single-cell RNA sequencing data for LUAD and adjacent lung tissues.
Fig. 3: Derlin-3 was activated in response to ER stress in plasma cells.
Fig. 4: Derlin-3 mediated IgG4 secretion in plasma cells via Hrd1/p38/PRDM1 axis.
Fig. 5: IgG4 promoted the transformation of macrophages to immunosuppressive M2 phenotype.
Fig. 6: Derlin-3-mediated M2 polarization further affected the proliferation and migration of LUAD cells.
Fig. 7: Knockdown of Derlin-3 suppressed tumorigenesis in vivo.
Fig. 8: The schematic diagram illustrates the proposed mechanism of Derlin-3 in the tumor microenvironment of LUAD.

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Data availability

The datasets presented in this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by Startup Fund for scientific research, Fujian Medical University (Grant number: 2021QH2044), High-level Talent Funding Project of Quanzhou, China (Grant number: 2020C001R), Quanzhou High-level Talent Introduction Program (Grant number: 2023CT014), and Fujian Province Science and Technology Innovation Joint Fund Project (Grant number: 2024Y9397).

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Author notes

  1. These authors contributed equally: Lanlan Lin, Luyang Chen, Guofu Lin.

Authors and Affiliations

  1. Fujian Provincial Clinical Research Center of Interventional Respirology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China

    Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen, Linlin Huang, Dongyong Yang, Yiming Zeng & Yuan Xu

  2. Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China

    Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen, Linlin Huang, Dongyong Yang & Yiming Zeng

  3. Fujian Provincial Key Laboratory of Lung Stem Cells, Quanzhou, Fujian Province, 362000, China

    Lanlan Lin, Luyang Chen, Guofu Lin, Xiaohui Chen & Yiming Zeng

  4. Department of Thoracic Surgery, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China

    Jiansheng Yang & Ronghang Lin

  5. Department of Pathology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China

    Shaohua Chen

  6. Department of Epidemiology and Health Statistics, The School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, 350122, China

    Fei He

  7. The Tumor Immunogenomics and Immunosurveillance (TIGI) Lab, UCL Cancer Institute, London, UK

    Danwen Qian

  8. Clinical Research Center, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian Province, 362000, China

    Yuan Xu

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Contributions

Y.X and Y.Z conceived and supervised the project. G.L and L.L performed the experiments, analyzed the data and wrote the manuscript, L.C assisted in part of the manuscript writing. X.C and F.H assisted with the computational analysis. D.Q was responsible for the analysis of single-cell transcriptomic data. J.Y and R.L collected surgical specimens and clinical records. S.C and D.Y conducted molecular pathological experiments and interpreted the results. L.H contributed to the peer review content modifications. All authors read and approved the final manuscript.

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Correspondence to Yiming Zeng or Yuan Xu.

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The study was approved by the Ethics Committee of the Second Affiliated Hospital of Fujian Medical University (approval No. 2022-89) following the principles of the Declaration of Helsinki, and written informed consents were obtained from all patients. Animal experiment was approved by the Institutional Animal Ethics Committee.

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Lin, L., Chen, L., Lin, G. et al. Derlin-3 manipulates the endoplasmic reticulum stress and IgG4 secretion of plasma cells in lung adenocarcinoma. Oncogene (2025). https://doi.org/10.1038/s41388-025-03435-8

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