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.

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有前途的方法。