在免疫治疗时代，仑伐替尼（LEN）在晚期肝细胞癌（HCC）序贯治疗中仍占有重要地位。然而，LEN 的持续治疗效果还不够，并且需要解决耐药性的发展。 Neuropilin-1 (NRP1) 已知可作为表皮生长因子受体 (EGFR)、Met 和血管内皮生长因子受体 2 (VEGFR2) 的辅助受体，据报道这些受体与 LEN 耐药有关。在本研究中，我们使用细胞培养和体内异种移植模型来评估 NRP1 在 HCC 获得 LEN 耐药性中的贡献以及 NRP1 作为治疗靶点的潜力。 LEN 耐药增加肝癌细胞中的 EGF/EGFR 和肝细胞生长因子 (HGF)/Met 信号传导以及血管内皮细胞中的 VEGFA/VEGFR2 和 HGF/Met 信号传导，从而促进细胞增殖、细胞迁移和血管生成。我们发现 NRP1 的激活对于增强这些信号传导至关重要。此外，NRP1抑制联合LEN治疗可协同提高对LEN耐药HCC的抗肿瘤作用，表明NRP1是一个有吸引力的治疗靶点。NEW

In the era of immunotherapy, lenvatinib (LEN) still holds an important position in the sequential treatment of advanced hepatocellular carcinoma (HCC). However, the sustained therapeutic effect of LEN is not sufficient, and there is a need to address the development of resistance. Neuropilin-1 (NRP1) is known to act as a coreceptor for epidermal growth factor receptor (EGFR), Met, and vascular endothelial growth factor receptor 2 (VEGFR2), which have been reported to be involved in LEN resistance. In this study, we used cell culture and in vivo xenograft models to evaluate the contribution of NRP1 in the acquisition of LEN resistance in HCC as well as the potential of NRP1 as a therapeutic target. LEN resistance increased EGF/EGFR and hepatocyte growth factor (HGF)/Met signaling in liver cancer cells and VEGFA/VEGFR2 and HGF/Met signaling in vascular endothelial cells, thereby promoting cell proliferation, cell migration, and angiogenesis. We found that activation of NRP1 is essential for the enhancement of these signaling. In addition, NRP1 inhibition combined with LEN therapy synergistically improved the antitumor effects against LEN-resistant HCC, indicating that NRP1 is an attractive therapeutic target.NEW & NOTEWORTHY We demonstrated that neuropilin-1 (NRP1) was an essential coreceptor mediating the activation of multiple signaling pathways in the acquisition of resistance to lenvatinib (LEN) in HCC. The addition of NRP1 inhibition to LEN had a synergistic antitumor effect on LEN-resistant HCC in culture and in vivo xenograft models.