英国癌症研究所Pascal Meier和Tencho Tenev共同合作，近期取得重要工作进展。他们研究提出，RIPK1特异性PROTAC降解剂通过增强免疫原性细胞死亡实现强效抗肿瘤活性。相关研究成果2024年5月23日在线发表于《免疫》杂志上。

据介绍，受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）作为一种关键的应激前哨，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，但其非催化支架功能介导强大的促存活信号。因此，癌症细胞可以劫持RIPK1以阻断坏死并逃避免疫检测。

研究人员开发了一种小分子蛋白水解靶向嵌合体（PROTAC），该嵌合体选择性降解人和小鼠RIPK1。PROTAC介导的RIPK1缺失使TNFR1和TLR3/4信号中枢失调，从而增强NF-κB、MAPK和IFN信号的输出。

此外，RIPK1降解同时促进RIPK3的激活和坏死诱导。研究人员进一步证明，RIPK1降解通过使癌症细胞对治疗诱导的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，PROTAC靶向RIPK1成为克服放射或免疫疗法耐药性，和增强抗癌治疗的一种有前景的方法。

附：英文原文

Title: A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death

Author: Jonathan Mannion, Valentina Gifford, Benjamin Bellenie, Winnie Fernando, Laura Ramos Garcia, Rebecca Wilson, Sidonie Wicky John, Savita Udainiya, Emmanuel C. Patin, Crescens Tiu, Angel Smith, Maria Goicoechea, Andrew Craxton, Nathalia Moraes de Vasconcelos, Naomi Guppy, Kwai-Ming J. Cheung, Nicholas J. Cundy, Olivier Pierrat, Alfie Brennan, Theodoros I. Roumeliotis, Graeme Benstead-Hume, John Alexander, Gareth Muirhead, Scott Layzell, Wenxin Lyu, Victoria Roulstone, Mark Allen, Holly Baldock, Arnaud Legrand, Florian Gabel, Natalia Serrano-Aparicio, Chris Starling, Hongyan Guo, Jason Upton, Mads Gyrd-Hansen, Marion MacFarlane, Benedict Seddon, Florence Raynaud, Ioannis Roxanis, Kevin Harrington, Syed Haider, Jyoti S. Choudhary, Swen Hoelder, Tencho Tenev, Pascal Meier

Issue&Volume: 2024-05-23

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.

DOI: 10.1016/j.immuni.2024.04.025

Source: https://www.cell.com/immunity/fulltext/S1074-7613(24)00230-9