CD4⁺FOXP3Exon2⁺ regulatory T cell frequency predicts breast cancer prognosis and survival

CD4⁺FOXP3⁺ regulatory T cells (T_regs) suppress immune responses to tumors, and their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several cancers, including breast cancer (BC). However, the properties of intratumoral T_regs remain largely unknown. Here, we found that a functionally distinct subpopulation of T_regs, expressing the FOXP3 Exon2 splicing variants, is prominent in patients with hormone receptor-positive BC with poor prognosis. Notably, a comprehensive examination of the TCGA validated FOXP3E2 as an independent prognostic marker in all other BC subtypes. We found that FOXP3E2 expression underlies BCs with defective mismatch repair and a stem-like signature and highlights pathways involved in tumor survival. Last, we found that the TME induces FOXP3E2 through the CXCL12/CXCR4 axis and confirmed the higher immunosuppressive capacity of FOXP3E2⁺ T_regs derived from patients with BC. Our study suggests that FOXP3E2⁺ T_regs might be used as an independent biomarker to predict BC prognosis and survival and to develop super-targeted immunotherapies.