Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor clinical outcomes. While immune checkpoint inhibitors (ICIs) have shown promise in TNBC, many patients remain unresponsive, highlighting the urgent need for new immunotherapeutic targets and mechanisms. CD160, a GPI-anchored receptor expressed on cytotoxic immune and endothelial cells, we have recently been proposed CD160 as a novel immune checkpoint inhibitor in solid tumors (Scheffges, Devy, et al. 2024). In this study, we investigated CD160 as a dual therapeutic target in TNBC, combining immunoregulatory and anti-angiogenic potential. Using a novel high-affinity monoclonal antibody against CD160, we demonstrate that targeting this receptor significantly inhibits pathological angiogenesis and promotes vascular normalization in vitro and ex vivo , without inducing cytotoxicity. These effects may contribute to enhanced immune infiltration and improved tumor perfusion, ultimately improving patient survival. To better understand CD160's mechanism of action, we explored its molecular interactions in human endothelial cells. Super-resolution microscopy and functional assays revealed that CD160 physically associates with LRP1, identifying it as a potential co-receptor involved in its vascular effects. These findings support the development of CD160-targeted immunotherapy as a promising strategy for TNBC, acting both as an immune checkpoint inhibitor and a modulator of the tumor vasculature. References : Scheffges C, Devy J, Giustiniani J, Francois S, Cartier L, Merrouche Y, Foussat A, Potteaux S, Bensussan A, Marie-Cardine A. Identification of CD160-TM as a tumor target on triple negative breast cancers: possible therapeutic applications. Breast Cancer Res. 2024 Feb 15;26(1):28. doi: 10.1186/s13058-024-01785-x. PMID: 38360636; PMCID: PMC10870674.