MiR-139 modulates CD8+ T cells exhaustion by targeting CD28 in breast cancer.

miR-139 acts as a tumor suppressor in breast cancer cells, yet its role within the tumor immune microenvironment (TIME) remains unclear. This study explores the dual functions of miR-139 in both tumor and immune cells, particularly its effect on CD8+ T cell function and chemokine-mediated immune recruitment. Bioinformatics analysis using TCGA and GEO data identified miR-139 as differentially expressed in breast cancer. Using samples from 32 patients, we detected elevated miR-139 levels in tumor-infiltrating CD8+ T cells compared with adjacent normal tissues. Further experiments confirmed that miR-139 directly targets CD28, leading to its downregulation. Concurrently, increased expression of exhaustion markers PD-1 and TIGIT was observed. Moreover, tumors with high miR-139 expression showed upregulation of T-cell-recruiting chemokines CX3CL1, CXCL12, and CXCL14. These results demonstrate that miR-139 promotes CD8+ T cell exhaustion via suppression of CD28 and facilitates chemokine-mediated T cell recruitment, highlighting its immunosuppressive role in breast cancer.