High-Fat Diet Promotes Tumor Immune Evasion via CD155 Upregulation in Colorectal Cancer.

Abstract

BACKGROUND: Obesity-induced metabolic stress impairs the efficacy of immune checkpoint blockade (ICB) therapy, but the mechanisms linking a high-fat diet (HFD) to immune suppression remain unclear. OBJECTIVE: To investigate how HFD-induced metabolic changes modulate the tumor immune microenvironment through the STAT3/CD155 axis. METHODS: Murine colorectal cancer models using control, CD155-overexpressing (CD155 OE), and STAT3 knockdown CT26 cells were established under normal or HFD conditions with anti - PD-L1 treatment. Tumor growth, immune infiltration, and gene expression were analyzed by flow cytometry, Western blotting, and chromatin immunoprecipitation. RESULTS: HFD impaired anti - PD-L1 efficacy and accelerated tumor growth. Mechanistically, HFD promoted STAT3 nuclear translocation and CD155 upregulation, reducing CD8T cell infiltration and enhancing regulatory T cell accumulation. Chromatin immunoprecipitation confirmed direct STAT3 binding to the CD155 promoter, while STAT3 knockdown reversed these effects and restored antitumor immunity in HFD-fed mice. CONCLUSION: HFD-induced metabolic stress drives immune evasion via the STAT3/CD155 axis. Targeting this pathway may improve ICB efficacy in obesity-related cancers.