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<p>The cellular mechanisms governing the change from pulmonary nodules to early-stage lung adenocarcinoma (LUAD) at single-cell resolution are not yet fully elucidated. In the present study, we employed single-nucleus RNA sequencing (snRNA-seq) on 44 pulmonary nodule and paired normal specimens to investigate this process. Within the epithelial compartment, alveolar type 2 (AT2) cells were categorized into high- and low-malignancy subclusters. Our differential expression analysis identified a significant upregulation of the transcription factor SMAD family member 3 (SMAD3) in the high-malignancy group, which was shown to enhance LUAD proliferation and migration. Mechanistically, intercellular adhesion molecule 1 (ICAM1) was established as a downstream target of SMAD3, playing a pivotal role in mediating intercellular crosstalk between malignant AT2 cells and lymphocytes. Specifically, the interaction between ICAM1 and immunosuppressive CD4<sup>+</sup> T cells and immune-eliminating CD8<sup>+</sup> T cells was found to dampen T cell-mediated antitumor response. In conclusion, these results reveal that the SMAD3-ICAM1 axis drives the malignant change from pulmonary nodules to early-stage LUAD, underscoring the potential of these molecules as biomarkers to inform diagnosis and surgical decision-making.</p>

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Single-nucleus sequencing dissects the malignant change of early lung adenocarcinoma: SMAD3 suppresses antitumor T cell immunity via ICAM1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Zhi Zheng,
  • Shuangqing Liao,
  • Chengfei Yang,
  • Yanqi Li,
  • Kai Wang,
  • Ziqi Huang,
  • Sijin Liu,
  • Zhuoxin Dai,
  • Xiaobing Liu,
  • Peng Dai,
  • Xufeng Deng,
  • Jigang Dai,
  • Quanxing Liu

摘要

The cellular mechanisms governing the change from pulmonary nodules to early-stage lung adenocarcinoma (LUAD) at single-cell resolution are not yet fully elucidated. In the present study, we employed single-nucleus RNA sequencing (snRNA-seq) on 44 pulmonary nodule and paired normal specimens to investigate this process. Within the epithelial compartment, alveolar type 2 (AT2) cells were categorized into high- and low-malignancy subclusters. Our differential expression analysis identified a significant upregulation of the transcription factor SMAD family member 3 (SMAD3) in the high-malignancy group, which was shown to enhance LUAD proliferation and migration. Mechanistically, intercellular adhesion molecule 1 (ICAM1) was established as a downstream target of SMAD3, playing a pivotal role in mediating intercellular crosstalk between malignant AT2 cells and lymphocytes. Specifically, the interaction between ICAM1 and immunosuppressive CD4+ T cells and immune-eliminating CD8+ T cells was found to dampen T cell-mediated antitumor response. In conclusion, these results reveal that the SMAD3-ICAM1 axis drives the malignant change from pulmonary nodules to early-stage LUAD, underscoring the potential of these molecules as biomarkers to inform diagnosis and surgical decision-making.