Immunotherapies targeting the programmed cell death-1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) pathway sparked a revolution in cancer treatment. These breakthrough therapies work by disrupting the interaction between PD-1—expressed on T cells—and its ligand PD-L1, commonly found on the surface of cancer cells. By using monoclonal antibodies to block this binding, the immune system is unleashed to fight cancer more effectively. However, PD-L1’s role extends far beyond immune evasion. When situated on cancer cells, PD-L1 transmits inhibitory signals through PD-1, silencing the effector functions of T cells. However, PD-L1 also engages in reverse signaling, also called intrinsic signaling, delivering intracellular instructions that contribute to cancer cell survival, even in the absence of PD-1 binding. This signaling cascade shields cancer cells from apoptosis, drives proliferation, regulates DNA damage responses, and even functions as a co-transcriptional transactivator, amplifying cancer’s ability to thrive. The intricate mechanisms behind PD-L1’s intrinsic signaling are under intense investigation. In this review, we provide a historical perspective on the discoveries leading to PD-L1’s structure, signaling motifs, and interacting partners, shedding light on its multifaceted roles and the promising therapeutic possibilities ahead.
靶向程序性细胞死亡配体1（PD-L1）与程序性细胞死亡蛋白1（PD-1）通路的免疫疗法引发了癌症治疗的革命。这类突破性疗法通过阻断T细胞表面表达的PD-1与癌细胞表面常见的配体PD-L1之间的相互作用，释放免疫系统以更有效地对抗癌症。然而，PD-L1的功能远不止于免疫逃逸。当位于癌细胞表面时，PD-L1通过PD-1传递抑制信号，使T细胞的效应功能失活。同时，PD-L1还参与反向信号传导（亦称内源性信号传导），即使在缺乏PD-1结合的情况下，也能传递促进癌细胞存活的细胞内指令。这一信号级联反应保护癌细胞免于凋亡，驱动细胞增殖，调控DNA损伤应答，甚至可作为共转录反式激活因子，增强癌细胞的生存能力。目前，PD-L1内源性信号传导背后的复杂机制正受到深入研究。本综述从历史视角梳理了PD-L1结构、信号基序及其相互作用蛋白的发现历程，揭示其多重生物学功能，并展望其潜在的治疗前景。
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