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.

中文翻译：

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用于 PD-L1 降解和减轻放射免疫治疗耐药性的可点击抑制剂的肿瘤特异性递送


在肿瘤中实现对程序性死亡配体 1 （PD-L1） 的选择性和持久抑制以激活 T 细胞仍然是免疫检查点阻断治疗的主要挑战。我们在这里提出了一组用于空间限制 PD-L1 降解和癌症放射免疫治疗的可点击抑制剂。使用代谢聚糖工程点击生物正交化学，用高活性叠氮化物基团标记肿瘤细胞膜上表达的 PD-L1。这使得可点击的抑制剂与 PD-L1 共价结合，并随后进行 PD-L1 降解。随后使用响应肿瘤细胞外酸性 pH 值的 pH 活化纳米颗粒将可点击的 PD-L1 抑制剂递送到细胞外肿瘤微环境中，以在体内消耗肿瘤细胞和巨噬细胞膜表面的 PD-L1。我们进一步证明，可点击的 PD-L1 抑制剂与放疗 （RT） 的组合通过抑制肿瘤组织中 RT 上调的 PD-L1 根除已建立的肿瘤。因此，通过可点击的 PD-L1 抑制剂选择性阻断肿瘤中的 PD-L1 提供了一种促进癌症免疫治疗的通用方法。