使用抗程序性死亡配体1（PD-L1）抗体的癌症免疫治疗已应用于各种临床应用并取得了一定的效果。然而，自身免疫、肿瘤过度进展和患者总体反应率低等限制阻碍了其进一步的临床应用。越来越多的证据表明，PD-L1 不仅存在于肿瘤细胞膜中，还存在于细胞质、外泌体甚至细胞核中。其中，肿瘤中PD-L1的动态和空间异质性表达是PD-L1抗体疗效不理想的主要原因。因此，大量研究集中在抑制或降解PD-L1以改善免疫反应，而全面了解PD-L1空间异质性的分子机制可以从根本上改变PD-L1抗体在临床开发中的现状。本文创造性地引入了PD-L1空间异质表达的概念，涵盖了多种PD-L1（包括mPD-L1、cPD-L1、nPD-L1和exoPD-L1）的结构和生物学功能。然后深入分析PD-L1的调控机制和潜在的治疗靶点，为未来的研究提供坚实的基础。此外，还总结了药物的现状，特别是针对这些新靶点的小分子调节剂的开发，为潜在的 PD-L1 治疗策略提供了新的视角。© 2023 作者。 《先进科学》由 Wiley-VCH GmbH 出版。

Cancer immunotherapy using anti-programmed death-ligand 1 (PD-L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD-L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD-L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD-L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD-L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD-L1 can fundamentally transform the current status of PD-L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD-L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD-L1 (including mPD-L1, cPD-L1, nPD-L1, and exoPD-L1). Then an in-depth analysis of the regulatory mechanisms and potential therapeutic targets of PD-L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD-L1 therapeutics strategies.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.