PDF(Pubmed)
Abstract：
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.
摘要：
受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）作为一个关键的应激前哨，协调细胞存活，炎症,和免疫原性细胞死亡（ICD）。尽管RIPK1的催化功能是触发细胞死亡所必需的，其非催化支架功能介导强大的促生存信号。因此，癌细胞可以劫持RIPK1来阻止坏死和逃避免疫检测。我们产生了选择性降解人和鼠RIPK1的小分子蛋白水解靶向嵌合体(PROTAC)。PROTAC介导的RIPK1耗尽下调TNFR1和TLR3/4信号中枢，增强NF-κB的输出，MAPK,和IFN信号。此外,RIPK1降解同时促进RIPK3活化和凋亡诱导。我们进一步证明，RIPK1降解通过使癌细胞对治疗诱导的TNF和干扰素敏感来增强放射疗法和免疫疗法的免疫刺激作用。这促进了ICD，抗肿瘤免疫，和持久的治疗反应。因此,通过PROTACs靶向RIPK1是克服放射疗法或免疫疗法耐药性并增强抗癌疗法的一种有前景的方法。
