Although targeting programmed death 1/programmed death ligand 1 (PD-1/PD-L1) has achieved durable responses and disease remission in patients with certain cancers, relatively low response rates and emerging resistance limit its clinical application. Hence, a more thorough understanding of regulatory mechanisms of the PD-1/PD-L1 axis is vital for developing combined therapeutic strategies to overcome hurdles of PD-1/PD-L1 blockade. Increasing evidence has demonstrated that PD-L1 can be secreted into the extracellular space or translocated into the nucleus, which also plays a critical role in regulating cancer immune evasion, tumorigenesis, and immunotherapy. In this review, we summarize these emerging roles of extracellular and nuclear PD-L1 and discuss future research directions and potential opportunities in translational medicine.

尽管靶向程序性死亡1/程序性死亡配体1（PD-1/PD-L1）在某些癌症患者中取得了持久的反应和疾病缓解，但相对较低的反应率和新出现的耐药性限制了其临床应用。因此，更透彻地了解 PD-1/PD-L1 轴的调节机制对于开发联合治疗策略以克服 PD-1/PD-L1 阻断的障碍至关重要。越来越多的证据表明，PD-L1 可以分泌到细胞外空间或转移到细胞核中，这在调节癌症免疫逃避、肿瘤发生和免疫治疗中也起着关键作用。在这篇综述中，我们总结了细胞外和细胞核 PD-L1 的这些新兴作用，并讨论了转化医学的未来研究方向和潜在机会。