三阴性乳腺癌（TNBC）迫切需要新疗法。我们发现 Ropporin-1 (ROPN1) 作为 T 细胞治疗 TNBC 的靶点。 ROPN1 在 90% 的原发性和转移性 TNBC 中表现出高且均一的表达，但在健康组织中则不然。通过免疫肽组学和预测检测 HLA-A2 结合肽，并用于从初始库中检索 T 细胞受体 (TCR)。将基因引入 T 细胞并进行严格选择后，我们检索到了针对表位 FLYTYIAKV 的高度特异性 TCR，该表位不识别来自替代来源蛋白质的非同源表位。值得注意的是，这种 TCR 介导了体外三维肿瘤样细胞和体内肿瘤细胞的杀伤作用，并且优于标准治疗药物。最后，表达该 TCR 并使用临床方案制造的 T 细胞产品满足了标准的安全性和有效性测定。总的来说，我们已经确定并临床前验证了 ROPN1 作为靶点，抗 ROPN1 TCR T 细胞作为绝大多数 TNBC 患者的治疗方法。

Triple-negative breast cancer (TNBC) shows an urgent need for new therapies. We discovered Ropporin-1 (ROPN1) as a target to treat TNBC with T-cells. ROPN1 showed high and homogenous expression in 90% of primary and metastatic TNBC but not in healthy tissues. HLA-A2-binding peptides were detected via immunopeptidomics and predictions and used to retrieve T-cell receptors (TCRs) from naïve repertoires. Following gene introduction into T-cells and stringent selection, we retrieved a highly specific TCR directed against the epitope FLYTYIAKV that did not recognize non-cognate epitopes from alternative source proteins. Notably, this TCR mediated killing of three-dimensional tumoroids in vitro and tumor cells in vivo and outperformed standard-of-care drugs. Finally, the T-cell product expressing this TCR and manufactured using a clinical protocol fulfilled standard safety and efficacy assays. Collectively, we have identified and preclinically validated ROPN1 as a target and anti-ROPN1 TCR T-cells as a treatment for the vast majority of TNBC patients.