School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
State Key Laboratory of Chemical Biology and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Sci Adv. 2024 Nov 15;10(46):eadq3940. doi: 10.1126/sciadv.adq3940.
Achieving selective and durable inhibition of programmed death ligand 1 (PD-L1) in tumors for T cell activation remains a major challenge in immune checkpoint blockade therapy. We herein presented a set of clickable inhibitors for spatially confined PD-L1 degradation and radioimmunotherapy of cancer. Using metabolic glycan engineering click bioorthogonal chemistry, PD-L1 expressed on tumor cell membranes was labeled with highly active azide groups. This enables covalently binding of the clickable inhibitor with PD-L1 and subsequent PD-L1 degradation. A pH-activatable nanoparticle responding to extracellular acidic pH of tumor was subsequently used to deliver the clickable PD-L1 inhibitor into extracellular tumor microenvironment for depleting PD-L1 on the surface of tumor cell and macrophage membranes in vivo. We further demonstrated that a combination of the clickable PD-L1 inhibitor with radiotherapy (RT) eradicated the established tumor by inhibiting RT-up-regulated PD-L1 in the tumor tissue. Therefore, selective PD-L1 blockade in tumors via the clickable PD-L1 inhibitor offers a versatile approach to promote cancer immunotherapy.
实现在肿瘤中选择性和持久性抑制程序性死亡配体 1（PD-L1）以激活 T 细胞仍然是免疫检查点阻断治疗的主要挑战。我们在此提出了一组用于空间限定的 PD-L1 降解和癌症放射性免疫治疗的点击抑制剂。利用代谢糖工程点击生物正交化学，将肿瘤细胞膜上表达的 PD-L1 用高活性叠氮基团标记。这使得点击抑制剂能够与 PD-L1 共价结合，并随后导致 PD-L1 降解。随后，一种对肿瘤细胞外酸性 pH 做出响应的 pH 激活纳米颗粒被用于将点击 PD-L1 抑制剂递送至细胞外肿瘤微环境中，以在体内耗尽肿瘤细胞膜和巨噬细胞膜上的 PD-L1。我们进一步证明，通过点击 PD-L1 抑制剂与放疗（RT）联合治疗，通过抑制肿瘤组织中 RT 上调的 PD-L1，消除了已建立的肿瘤。因此，通过点击 PD-L1 抑制剂在肿瘤中选择性地阻断 PD-L1 为促进癌症免疫治疗提供了一种多功能方法。
