Programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here, we verify that triple-negative breast cancer (TNBC) has higher PD-L1 expression than other subtypes. We then discover that nucleophosmin (NPM1) binds to PD-L1 promoter specifically in TNBC cells and activates PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrate that PARP1 suppresses PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which is required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevates PD-L1 expression in TNBC and exerts a better effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.

程序性细胞死亡蛋白-1（PD-1）/程序性细胞死亡配体-1（PD-L1）相互作用在肿瘤相关的免疫逃逸中起着至关重要的作用。在这里，我们验证三阴性乳腺癌（TNBC）具有比其他亚型更高的PD-L1表达。然后，我们发现，核磷蛋白（NPM1）与TNBC细胞中的PD-L1启动子结合，并激活PD-L1转录，从而在体外和体内抑制T细胞活性。此外，我们证明PARP1通过其与NPM1的核酸结合域的相互作用来抑制PD-L1转录，这是NPM1在PD-L1启动子上结合所必需的。一致地，PARP1抑制剂奥拉帕尼可升高PD-L1在TNBC中表达，并在抗PD-L1治疗中发挥更好的作用。总之，我们的研究表明NPM1是TNBC中PD-L1的转录调节因子，这可能会导致潜在的治疗策略，以增强癌症免疫疗法的功效。