The blood-brain barrier (BBB) limits conventional antibody-based approaches to brain tumors. ENT2, an equilibrative nucleoside transporter, facilitates penetration of autoantibodies into live cells and is expressed in the BBB. PAT-DX1 (also known as Deoxymab-1 or DX1) is an ENT2-dependent, cell-penetrating, and DNA-damaging lupus autoantibody that is synthetically lethal to cancer cells with defects in the DNA damage response. PTEN loss renders sensitivity to DX1 and is common in primary and metastatic brain tumors. We show that DX1 is toxic to spheroids derived from primary PTEN-deficient glioblastoma (GBM), and crosses the BBB to suppress the growth of orthotopic GBM and breast cancer brain metastases. Mechanistically, we find the ENT2 inhibitor dipyridamole blocks DX1 penetration into brain endothelial cells and transport across the BBB in vitroand in vivo, consistent with ENT2-mediated uptake of DX1 into brain tumors. Autoantibodies that hijack nucleoside transporters to cross cell membranes may open new frontiers in brain tumor therapy.