The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.

受体相互作用蛋白激酶 1 （RIPK1） 的支架功能赋予对免疫检查点阻断 （ICB） 的内在和外在耐药性，并成为改善癌症免疫疗法的有前途的靶点。为了解决 RIPK1 中间结构域内定义不明确的结合口袋所带来的挑战，我们在这里利用蛋白水解靶向嵌合体 （PROTAC） 技术开发 RIPK1 降解剂 LD4172。LD4172 在体外和体内均表现出有效的选择性 RIPK1 降解。LD4172 降解 RIPK1 会触发雌性 C57BL/6J 小鼠的免疫原性细胞死亡，增强肿瘤浸润淋巴细胞反应，并使肿瘤对抗 PD1 治疗敏感。这项工作报道了一种 RIPK1 降解剂，它用作研究 RIPK1 支架功能的化学探针，并作为增强肿瘤对 ICBs 治疗反应的潜在治疗剂。