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

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.