乳腺癌发展过程中，编程细胞死亡1配体1（PD-L1）在中性粒细胞中的过度表达导致延迟的细胞凋亡，并促进中性粒细胞在肺部的高增殖，形成一个有利于肺转移的预转移基质。已知具有抗炎和抗肿瘤作用的三萜皂苷类化合物Platycodin D（PlaD）据报道可以下调PD-L1的表达。本研究旨在研究PlaD对4T1肿瘤小鼠中中性粒细胞PD-L1的抑制作用，以及乳腺癌肺转移的潜在机制。在该研究中，利用原位4T1小鼠乳腺癌模型，采用灌胃给予10和20 mg/kg的PlaD。PlaD有效地降低了预转移期骨髓、外周血和肺组织中过多中性粒细胞的数量以及它们的高迁移能力，从而有效地抑制肿瘤生长和肺转移。此外，PlaD通过减少中性粒细胞PD-L1的表达来抑制磷脂酰肌醇-3-激酶（PI3K）/Akt信号通路，并促进中性粒细胞的凋亡。体外实验中，PlaD处理剂量依赖地降低了类中性粒细胞dHL-60的存活能力和迁移能力。同样，PlaD抑制了IFN-γ刺激引起的PD-L1的增加，并随后诱导dHL-60细胞的凋亡。总之，PlaD的给予通过降低中性粒细胞PD-L1的表达，抑制PI3K/Akt信号通路。PlaD促进中性粒细胞凋亡，从而抑制预转移基质的形成，最终阻断肺转移的发展。 版权所有 © 2023作者。由Elsevier B.V.出版。保留所有权利。

During breast cancer development, programmed cell death 1 ligand 1 (PD-L1) overexpression in neutrophils leads to delayed apoptosis and promotes neutrophil hyperproliferation in the lung to form a premetastatic niche, which is beneficial for pulmonary metastasis. Platycodin D (PlaD), a triterpenoid saponin with known anti-inflammatory and antitumor effects, has been reported to downregulate PD-L1 expression. This study aimed to investigate the inhibitory effect of PlaD on neutrophil PD-L1 in 4 T1 tumor-bearing mice and the potential mechanism of breast cancer pulmonary metastasis. In this study, the orthotopic 4 T1 murine mammary carcinoma model was administered 10 and 20 mg/kg PlaD by gavage. PlaD reduced the excess neutrophils and decreased their high migratory capacity in bone marrow, peripheral blood and lung tissue in the premetastatic period, thereby effectively inhibiting tumor growth and pulmonary metastasis. Moreover, PlaD inhibited the phosphatidylinositol-3-kinase (PI3K)/Akt pathway by decreasing the expression of PD-L1 in neutrophils and promoted neutrophil apoptosis. In vitro, PlaD treatment decreased the viability and inhibited migration of neutrophil-like dHL-60 in a dose-dependent manner. Similarly, PlaD inhibited the increase in PD-L1 induced by IFN-γ stimulation and subsequently induced apoptosis in dHL-60 cells. In conclusion, the administration of PlaD inhibited the PI3K/Akt signaling pathway by reducing the expression of PD-L1 in neutrophils. PlaD promoted neutrophil apoptosis, thereby inhibiting the establishment of a premetastatic niche and ultimately blocking the development of pulmonary metastasis.Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.