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Background <p>Lung adenocarcinoma (LUAD) frequently harbors activating mutations in the epidermal growth factor receptor (EGFR), making EGFR tyrosine kinase inhibitors (EGFR-TKIs) a critical component of targeted therapy. Although third-generation EGFR-TKIs, such as Furmonertinib, have improved outcomes for patients with EGFR-mutant LUAD, drug resistance and tumor adaptation remain major challenges. The cellular and molecular mechanisms underlying response and adaptation to Furmonertinib, particularly within the tumor microenvironment (TME), are not fully understood.</p> Methods <p>We performed single-cell RNA sequencing on tumor and paired paracancerous tissues from EGFR-positive LUAD patients before and after Furmonertinib treatment, integrating both public and in-house datasets. We systematically analyzed changes in cellular composition, gene expression profiles, pathway enrichment, and ligand–receptor-mediated cell–cell communication.</p> Results <p>Furmonertinib treatment led to a marked reduction in tumor cell proportion and profound remodeling of the TME. There was an increase in T cell infiltration, particularly CD4<sup>+</sup> T cells, and a decrease in exhausted CD8<sup>+</sup> T cells, indicating a shift toward a less immunosuppressive microenvironment. Cancer-associated fibroblasts and monocytes were also enriched post-treatment. Tumor cells exhibited increased EGFR expression, along with transcriptomic reprogramming characterized by upregulation of signaling, immune, and differentiation pathways, and downregulation of metabolic and protein synthesis genes. Cell–cell communication analysis revealed attenuation of immunosuppressive signaling (such as MIF axis) and enhancement of alternative ligand–receptor interactions, including LAMC1- and EGFR-related pathways.</p> Conclusions <p>Our integrative single-cell analysis reveals that Furmonertinib therapy induces significant cellular and molecular changes in EGFR-positive LUAD, including TME remodeling, transcriptomic adaptation, and reprogramming of intercellular communication networks. These findings provide insight into the mechanisms of Furmonertinib response and resistance, and may inform strategies to optimize EGFR-TKI therapy.</p>

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Single-cell transcriptomic analysis reveals cellular and molecular changes in EGFR-positive lung adenocarcinoma before and after Furmonertinib treatment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月27日

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  • Jian Chen,
  • Minghui Cai,
  • Lifei Meng,
  • Ze Hong,
  • Wentao Hu

摘要

Background

Lung adenocarcinoma (LUAD) frequently harbors activating mutations in the epidermal growth factor receptor (EGFR), making EGFR tyrosine kinase inhibitors (EGFR-TKIs) a critical component of targeted therapy. Although third-generation EGFR-TKIs, such as Furmonertinib, have improved outcomes for patients with EGFR-mutant LUAD, drug resistance and tumor adaptation remain major challenges. The cellular and molecular mechanisms underlying response and adaptation to Furmonertinib, particularly within the tumor microenvironment (TME), are not fully understood.

Methods

We performed single-cell RNA sequencing on tumor and paired paracancerous tissues from EGFR-positive LUAD patients before and after Furmonertinib treatment, integrating both public and in-house datasets. We systematically analyzed changes in cellular composition, gene expression profiles, pathway enrichment, and ligand–receptor-mediated cell–cell communication.

Results

Furmonertinib treatment led to a marked reduction in tumor cell proportion and profound remodeling of the TME. There was an increase in T cell infiltration, particularly CD4+ T cells, and a decrease in exhausted CD8+ T cells, indicating a shift toward a less immunosuppressive microenvironment. Cancer-associated fibroblasts and monocytes were also enriched post-treatment. Tumor cells exhibited increased EGFR expression, along with transcriptomic reprogramming characterized by upregulation of signaling, immune, and differentiation pathways, and downregulation of metabolic and protein synthesis genes. Cell–cell communication analysis revealed attenuation of immunosuppressive signaling (such as MIF axis) and enhancement of alternative ligand–receptor interactions, including LAMC1- and EGFR-related pathways.

Conclusions

Our integrative single-cell analysis reveals that Furmonertinib therapy induces significant cellular and molecular changes in EGFR-positive LUAD, including TME remodeling, transcriptomic adaptation, and reprogramming of intercellular communication networks. These findings provide insight into the mechanisms of Furmonertinib response and resistance, and may inform strategies to optimize EGFR-TKI therapy.