受体相互作用丝氨酸/苏氨酸蛋白激酶 1 (RIPK1) 作为协调细胞存活、炎症和免疫原性细胞死亡 (ICD) 的关键应激哨兵发挥作用。尽管 RIPK1 的催化功能是触发细胞死亡所必需的，但其非催化支架功能可介导强的促生存信号传导。因此，癌细胞可以劫持 RIPK1 以阻止坏死性凋亡并逃避免疫检测。我们生成了一种小分子蛋白水解靶向嵌合体 (PROTAC)，它可以选择性降解人类和小鼠 RIPK1。 PROTAC 介导的 RIPK1 耗竭会解除 TNFR1 和 TLR3/4 信号中枢的调节，从而增强 NF-κB、MAPK 和 IFN 信号传导的输出。此外，RIPK1 降解同时促进 RIPK3 激活和坏死性凋亡诱导。我们进一步证明，RIPK1 降解通过使癌细胞对治疗诱导的 TNF 和干扰素敏感，增强了放射治疗和免疫治疗的免疫刺激作用。这促进了 ICD、抗肿瘤免疫力和持久的治疗反应。因此，通过 PROTAC 靶向 RIPK1 成为克服放射或免疫治疗耐药性并增强抗癌治疗的一种有前景的方法。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.