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Background <p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of MHC-I molecules, thereby weakening CD8⁺ T cell–mediated immune surveillance. However, whether PCSK9 additionally regulates immune infiltration through the tumor vascular barrier remains unknown.</p> Methods <p>This study employed a colorectal cancer (CRC) organoid–T cell coculture system, human umbilical vein endothelial cell (HUVEC) barrier assays, and a patient-derived orthotopic xenograft (PDOX) liver metastasis model. PCSK9 was knocked down to assess its effects on antigen presentation, T cell activation, endothelial integrity, and tumor growth.</p> Results <p>PCSK9 knockdown significantly upregulated MHC-I expression, enhanced CD8⁺ T cell activation and cytotoxicity, and induced high production of IFN-γ and TNF-α. These cytokines disrupted VE-cadherin–mediated endothelial junctions, reduced transendothelial electrical resistance (TEER), increased vascular permeability, and promoted deep T cell infiltration, ultimately suppressing tumor growth. Consistent in vitro and in vivo findings provided closed-loop validation from molecular to histological levels.</p> Conclusions <p>For the first time, this study reveals that PCSK9 establishes a multilevel immunoregulatory axis spanning antigen presentation, T cell activation, and the vascular barrier, driving immune evasion and microenvironmental remodeling in CRC. Inhibition of PCSK9 simultaneously activates antitumor immunity and optimizes the vascular microenvironment, presenting a promising combinatorial therapeutic target against CRC metastasis.</p>

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PCSK9 orchestrates the antigen presentation–endothelial barrier axis to potentiate immune exclusion in colorectal cancer

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Gang Wang,
  • Zengyaran Yue,
  • Yong Bian,
  • Tingting Su,
  • Hengyi Qi,
  • Yuwei Zhang,
  • Xu Wang,
  • Weiwei He,
  • Zhongqing Liang,
  • Gang Yin,
  • Decai Tang

摘要

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of MHC-I molecules, thereby weakening CD8⁺ T cell–mediated immune surveillance. However, whether PCSK9 additionally regulates immune infiltration through the tumor vascular barrier remains unknown.

Methods

This study employed a colorectal cancer (CRC) organoid–T cell coculture system, human umbilical vein endothelial cell (HUVEC) barrier assays, and a patient-derived orthotopic xenograft (PDOX) liver metastasis model. PCSK9 was knocked down to assess its effects on antigen presentation, T cell activation, endothelial integrity, and tumor growth.

Results

PCSK9 knockdown significantly upregulated MHC-I expression, enhanced CD8⁺ T cell activation and cytotoxicity, and induced high production of IFN-γ and TNF-α. These cytokines disrupted VE-cadherin–mediated endothelial junctions, reduced transendothelial electrical resistance (TEER), increased vascular permeability, and promoted deep T cell infiltration, ultimately suppressing tumor growth. Consistent in vitro and in vivo findings provided closed-loop validation from molecular to histological levels.

Conclusions

For the first time, this study reveals that PCSK9 establishes a multilevel immunoregulatory axis spanning antigen presentation, T cell activation, and the vascular barrier, driving immune evasion and microenvironmental remodeling in CRC. Inhibition of PCSK9 simultaneously activates antitumor immunity and optimizes the vascular microenvironment, presenting a promising combinatorial therapeutic target against CRC metastasis.