Gut Microbiota-Induced CTLA4 Expression on CD8+ T Cells Impairs Antitumor Immunity and Promotes Colorectal Cancer Progression.

Abstract

This study reveals a novel gut microbiota-CD8⁺ T cell axis driving immunosuppression in colorectal cancer. Analysis of 16S rRNA sequencing identified significant gut dysbiosis in CRC patients, with marked enrichment of Phocaeicola and Bacteroides. Single-cell transcriptomics uncovered substantial T cell depletion and elevated CTLA4⁺PD1⁺ immune cells within the tumour microenvironment. Critically, spatial transcriptomics demonstrated co-localization of CTLA4⁺CD8⁺ T cells with tumour cells, indicating direct immunosuppressive interactions. Functional validation confirmed CTLA4 overexpression impairs CD8⁺ T cell effector capacity, accelerating CRC cell proliferation and invasion. In vivo models demonstrated that faecal microbiota transplantation (FMT) promoted CTL activation, reduced Bacteroides abundance, decreased the formation of CD8⁺CTLA4⁺ T cells and ameliorated CRC symptoms. Additionally, CTLA4 knockdown inhibited tumour growth and metastasis. These findings establish a mechanistic pathway: gut dysbiosis induces chronic inflammation, triggering CTLA4 upregulation on CD8⁺ T cells to promote T cell exhaustion and tumour immune evasion. The study provides immunological evidence for targeting the microbiota-CTLA4 axis in CRC immunotherapy.