净蛋白-1在癌症中作为促肿瘤机制进行上调。在这里，我们描述净蛋白-1在大多数人类子宫内膜癌（ECs）中的上调，并且证明使用抗净蛋白-1抗体（NP137）抑制净蛋白-1在EC小鼠模型中对肿瘤进展的有效性。接下来，我们对14例晚期EC患者进行了一项第一类单药试验，评估了NP137的疗效。作为最佳反应，我们观察到其中有8例稳定疾病（占14例的57.1%），并且有1例符合RECIST v.1.1的客观反应（部分缓解，占14例的7.1%），在6周内目标病灶减小了51.16％，在随后的6个月内减小了54.65％。为了评估NP137的作用机制，我们进行了小鼠肿瘤基因组学分析，除了诱导细胞死亡外，我们观察到NP137还抑制了上皮-间充质转化（EMT）。通过对NP137试验的EC患者术前和术后活检进行了批量RNA测序（RNA-seq）、空间转录组学和单细胞RNA测序，我们注意到肿瘤的EMT整体减少。这与免疫浸润的改变和癌细胞与肿瘤微环境间的增加相互作用相关。鉴于EMT在对当前标准治疗的抵抗中的重要性，我们在EC小鼠模型中展示了NP137与卡铂-紫杉醇的联合疗法超过了单独使用卡铂-紫杉醇。我们的结果确定净蛋白-1抑制是一种临床策略，可同时触发肿瘤减灭和EMT抑制，从而潜在地减轻对标准治疗的抵抗。© 2023. 作者（s）。

Netrin-1 is upregulated in cancers as a protumoural mechanism1. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.© 2023. The Author(s).