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Objective <p>This study aimed to elucidate the mechanism by which SHP2 binding to PD-1 on T cells induces T cell exhaustion via the regulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway, and its functional implications in thyroid cancer.</p> Methods <p>First, single-cell RNA sequencing analysis was performed to characterize the tumor immune microenvironment, with a specific focus on the functional status of CD4 + regulatory T cells (Tregs). Bioinformatics analyses of TCGA and GTEx datasets were then conducted to evaluate the differential expression of SHP2, STAT3, BRD4, and NFAT2. Finally, the effects of SHP2 overexpression, PD-1 knockdown, and BRD4 knockdown on tumor growth and T cell function were examined using a nude mouse tumor xenograft model and in vitro cell culture assays. Multiple techniques, including Western blot, ELISA, flow cytometry, scratch wound assay, and Transwell assay, were applied to verify the regulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway by SHP2-PD-1 binding and its impacts on T cell exhaustion and thyroid cancer cell phenotypes.</p> Results <p>Single-cell analysis demonstrated that CD4 + Tregs in papillary thyroid carcinoma displayed significantly elevated exhaustion and proliferation scores relative to normal thyroid tissues. In addition, pathway enrichment and pseudotime trajectory analyses revealed that Tregs within the tumor microenvironment were progressively transitioning toward a severe exhaustion state, driven by the upregulation of core signaling molecules. Bioinformatics analysis showed that SHP2, STAT3, BRD4, and NFAT2 were markedly overexpressed in thyroid cancer tissues, and high SHP2 expression was positively correlated with T cell exhaustion markers (e.g., TIM3, LAG3, TIGIT). In the nude mouse xenograft model, SHP2 overexpression significantly promoted tumor growth, while PD-1 or BRD4 knockdown inhibited tumor progression. In vitro cellular assays further confirmed that SHP2 interaction with PD-1 triggered T cell exhaustion through the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling cascade, thereby modulating thyroid cancer cell migration, invasion, and apoptosis.</p> Conclusion <p>SHP2–PD-1 interaction in T cells elicits T cell exhaustion via modulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway, thereby accelerating thyroid cancer progression. These findings identify a novel potential therapeutic target for thyroid cancer immunotherapy.</p>

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SHP2–PD-1 interaction in T cells induces T cell exhaustion via modulation of AMPK/STAT3/EGR1/BRD4/NFAT2 signaling in thyroid cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • Jin Xiao,
  • Bo Wang,
  • Hao Guo,
  • Suyuan Zhao,
  • Wentao Zhang,
  • Zhibo Yin

摘要

Objective

This study aimed to elucidate the mechanism by which SHP2 binding to PD-1 on T cells induces T cell exhaustion via the regulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway, and its functional implications in thyroid cancer.

Methods

First, single-cell RNA sequencing analysis was performed to characterize the tumor immune microenvironment, with a specific focus on the functional status of CD4 + regulatory T cells (Tregs). Bioinformatics analyses of TCGA and GTEx datasets were then conducted to evaluate the differential expression of SHP2, STAT3, BRD4, and NFAT2. Finally, the effects of SHP2 overexpression, PD-1 knockdown, and BRD4 knockdown on tumor growth and T cell function were examined using a nude mouse tumor xenograft model and in vitro cell culture assays. Multiple techniques, including Western blot, ELISA, flow cytometry, scratch wound assay, and Transwell assay, were applied to verify the regulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway by SHP2-PD-1 binding and its impacts on T cell exhaustion and thyroid cancer cell phenotypes.

Results

Single-cell analysis demonstrated that CD4 + Tregs in papillary thyroid carcinoma displayed significantly elevated exhaustion and proliferation scores relative to normal thyroid tissues. In addition, pathway enrichment and pseudotime trajectory analyses revealed that Tregs within the tumor microenvironment were progressively transitioning toward a severe exhaustion state, driven by the upregulation of core signaling molecules. Bioinformatics analysis showed that SHP2, STAT3, BRD4, and NFAT2 were markedly overexpressed in thyroid cancer tissues, and high SHP2 expression was positively correlated with T cell exhaustion markers (e.g., TIM3, LAG3, TIGIT). In the nude mouse xenograft model, SHP2 overexpression significantly promoted tumor growth, while PD-1 or BRD4 knockdown inhibited tumor progression. In vitro cellular assays further confirmed that SHP2 interaction with PD-1 triggered T cell exhaustion through the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling cascade, thereby modulating thyroid cancer cell migration, invasion, and apoptosis.

Conclusion

SHP2–PD-1 interaction in T cells elicits T cell exhaustion via modulation of the AMPK/STAT3/EGR1/BRD4/NFAT2 signaling pathway, thereby accelerating thyroid cancer progression. These findings identify a novel potential therapeutic target for thyroid cancer immunotherapy.