CD2–CD58 axis orchestrates cytotoxic T lymphocyte function and metabolic crosstalk in breast cancer brain metastasis

Abstract This study investigates the impact of the CD2–CD58 signaling axis on effector T cell function and tumor metabolic crosstalk in breast cancer brain metastasis (BCBM) using single‐cell transcriptomic analysis. scRNA‐seq data analysis revealed the critical role of CD2–CD58 signaling between CD8 + T cells and tumor cells in BCBM. Functional assays demonstrated that CD2 knockdown inhibited cytotoxic T lymphocyte (CTL) proliferation, activation, and cytotoxicity, leading to impaired tumor cell recognition and enhanced proliferation, migration, and invasion. In vivo studies showed that CD2‐deficient CTLs promoted tumor growth and brain metastasis while affecting metabolic reprogramming by altering key enzyme expressions in pyrimidine biosynthesis and arginine metabolism pathways. The findings suggest that CD2 enhances CTL function against tumor cells and influences their metabolic states, highlighting the role of CD2 in remodeling the brain metastatic microenvironment in breast cancer.