Department of Urology, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, China.
Second Ward of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, 110042, China.
Mol Cancer. 2024 Sep 2;23(1):183. doi: 10.1186/s12943-024-02095-8.
Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.
程序性死亡受体-1（PD-1）及其配体程序性死亡配体-1（PD-L1）是调节免疫反应的关键分子。PD-L1 在各种免疫细胞、上皮细胞和癌细胞中持续表达，作为一种共刺激分子，能够损害 T 细胞介导的免疫反应。PD-1/PD-L1 相互作用在激活的 T 细胞上与 PD-1 结合后，触发信号通路，可诱导 T 细胞凋亡或无能，从而促进肿瘤的免疫逃逸。在包括膀胱癌（BCa）、肾细胞癌（RCC）和前列腺癌（PCa）在内的泌尿系统癌症中，PD-L1 的上调已被证实与预后不良和增强肿瘤免疫逃逸有关。最近的研究强调了 PD-1/PD-L1 轴在泌尿系统癌症免疫逃逸机制中的重要作用。PD-L1 和 T 细胞上的 PD-1 之间的相互作用通过抑制 T 细胞的激活和增殖进一步导致免疫抑制。PD-1/PD-L1 检查点抑制剂的临床应用在治疗晚期泌尿系统癌症方面显示出了有希望的疗效，显著改善了患者的预后。然而，对这些治疗的耐药性，无论是内在的还是获得性的，仍然是一个重大挑战。本综述旨在全面概述 PD-1/PD-L1 信号通路在泌尿系统癌症中的作用。我们总结了 PD-1 和 PD-L1 表达和活性的调节机制，包括遗传、表观遗传、转录后和翻译后修饰。此外，我们还讨论了 PD-1/PD-L1 抑制剂的当前临床研究、它们的治疗潜力以及与耐药性相关的挑战。了解这些机制对于开发克服治疗限制和增强癌症免疫治疗效果的新策略至关重要。
