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<p>Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells, disrupting CD8<sup>+</sup> T cell migration and anti-tumor function. To address this, we developed an innovative siRNA-based therapeutic approach targeting CXCL12 in CAFs. Using lipid nanocarriers (LNCs) as delivery vehicles, we engineered LNCs@si-CXCL12 nanoparticles to specifically silence CXCL12 expression in CAFs. In vitro studies demonstrated that LNCs@si-CXCL12 restored CD8<sup>+</sup> T cell migration and inhibited ESCC cell proliferation and migration. In vivo experiments in a spontaneous ESCC mouse model showed that CXCL12 silencing through nanoparticle delivery significantly reduced tumor growth, enhanced CD8<sup>+</sup> T cell-mediated tumoricidal activity, and improved overall survival. These findings highlight the potential of siRNA-loaded nanoparticles targeting CXCL12 as a novel therapeutic strategy to reprogram the immunosuppressive TME and enhance immune responses in ESCC. This approach provides a promising avenue for improving treatment outcomes and overcoming immune evasion in ESCC.</p> Graphical abstract <p></p>

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CXCL12-targeting siRNA nanoparticles alleviate immunosuppression and inhibit tumor progression in esophageal squamous cell carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月16日

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  • Shuyao Zhang,
  • Hong Jiang,
  • Chengkuan Zhao,
  • Yanli Lei,
  • Shaojie Liu,
  • Chengcheng Xu,
  • Xiaoshan Chen,
  • Danling Zheng,
  • Xiaolong Wu,
  • Xinyue Lin,
  • Wang Chen,
  • Yun Chen,
  • Jianxiang Huang,
  • XiaoLong Wei,
  • Yihui Huang,
  • Chaoxian Lin

摘要

Esophageal squamous cell carcinoma (ESCC) is associated with a highly immunosuppressive tumor microenvironment (TME), driven in part by cancer-associated fibroblasts (CAFs) that promote immune evasion through the secretion of CXCL12. CXCL12 interacts with the CXCR4 receptor on immune cells, disrupting CD8+ T cell migration and anti-tumor function. To address this, we developed an innovative siRNA-based therapeutic approach targeting CXCL12 in CAFs. Using lipid nanocarriers (LNCs) as delivery vehicles, we engineered LNCs@si-CXCL12 nanoparticles to specifically silence CXCL12 expression in CAFs. In vitro studies demonstrated that LNCs@si-CXCL12 restored CD8+ T cell migration and inhibited ESCC cell proliferation and migration. In vivo experiments in a spontaneous ESCC mouse model showed that CXCL12 silencing through nanoparticle delivery significantly reduced tumor growth, enhanced CD8+ T cell-mediated tumoricidal activity, and improved overall survival. These findings highlight the potential of siRNA-loaded nanoparticles targeting CXCL12 as a novel therapeutic strategy to reprogram the immunosuppressive TME and enhance immune responses in ESCC. This approach provides a promising avenue for improving treatment outcomes and overcoming immune evasion in ESCC.

Graphical abstract