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Purpose <p>To investigate the role and molecular mechanism of the NECTIN3-TIGIT axis in melanoma lymph node metastasis.</p> Methods <p>Single-cell RNA sequencing was performed on human primary melanoma and lymph node metastatic tissues. A tumor lymph node metastasis-on-a-chip model incorporating vascular, lymphatic, and dual-tumor modules was constructed, along with in vitro coculture systems using CD8<sup>+</sup> T cells and regulatory T cells. Functional blockade was achieved via NECTIN3 knockdown, TIGIT inhibitor (Tiragolumab), and combined antiPD1 therapy.</p> Results <p>The NECTIN3-TIGIT axis was identified as a core immune ligand-receptor pair in the highmetastasis subgroup, associated with increased regulatory T cell infiltration and CD8<sup>+</sup> T cell exhaustion. Both NECTIN3 and TIGIT expression were significantly elevated in metastatic lesions and correlated with reduced overall survival. The chip model recapitulated melanoma lymphatic migration and confirmed the immunosuppressive microenvironment. Mechanistically, the NECTIN3-TIGIT axis induced CD8<sup>+</sup> T cell exhaustion via the SHIP-1/TRAF6 pathway and promoted regulatory T cell activation by inhibiting AKT/mTORC1 signaling. NECTIN3 knockdown or Tiragolumab treatment suppressed tumor lymphatic migration, while combined antiPD1 and Tiragolumab most effectively reversed T cell exhaustion, impaired regulatory T cell function, and reduced metastasis.</p> Conclusion <p>The NECTIN3-TIGIT axis promotes melanoma lymph node metastasis by remodeling the immunosuppressive microenvironment. Combined blockade of NECTIN3-TIGIT and PD1 pathways represents a promising therapeutic strategy.</p>

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Tumor lymph node metastasis chip reveals that the NECTIN3-TIGIT axis promotes melanoma metastasis by enhancing treg cell function and inducing CD8+ T cell exhaustion

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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  • Cuihao Song,
  • Wenwei Zhu,
  • Yaolin Li,
  • Yuhan Ji,
  • Xiaoling Liu,
  • Yingjie Zhang,
  • Xiaoning Zhang,
  • Fangfang Wei,
  • Hexi Yang,
  • Likeng Liang,
  • Shuyan Huang,
  • Chengxin Li,
  • Yong Zhou

摘要

Purpose

To investigate the role and molecular mechanism of the NECTIN3-TIGIT axis in melanoma lymph node metastasis.

Methods

Single-cell RNA sequencing was performed on human primary melanoma and lymph node metastatic tissues. A tumor lymph node metastasis-on-a-chip model incorporating vascular, lymphatic, and dual-tumor modules was constructed, along with in vitro coculture systems using CD8+ T cells and regulatory T cells. Functional blockade was achieved via NECTIN3 knockdown, TIGIT inhibitor (Tiragolumab), and combined antiPD1 therapy.

Results

The NECTIN3-TIGIT axis was identified as a core immune ligand-receptor pair in the highmetastasis subgroup, associated with increased regulatory T cell infiltration and CD8+ T cell exhaustion. Both NECTIN3 and TIGIT expression were significantly elevated in metastatic lesions and correlated with reduced overall survival. The chip model recapitulated melanoma lymphatic migration and confirmed the immunosuppressive microenvironment. Mechanistically, the NECTIN3-TIGIT axis induced CD8+ T cell exhaustion via the SHIP-1/TRAF6 pathway and promoted regulatory T cell activation by inhibiting AKT/mTORC1 signaling. NECTIN3 knockdown or Tiragolumab treatment suppressed tumor lymphatic migration, while combined antiPD1 and Tiragolumab most effectively reversed T cell exhaustion, impaired regulatory T cell function, and reduced metastasis.

Conclusion

The NECTIN3-TIGIT axis promotes melanoma lymph node metastasis by remodeling the immunosuppressive microenvironment. Combined blockade of NECTIN3-TIGIT and PD1 pathways represents a promising therapeutic strategy.