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

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 CTLA4PD1 immune cells within the tumour microenvironment. Critically, spatial transcriptomics demonstrated co-localization of CTLA4CD8 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 CD8CTLA4 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.