RIPK1 at the interface between cell death and immunity
Loading...
Embargo End Date
2025-05-25
ICR Authors
Authors
Mannion, J
Document Type
Thesis or Dissertation
Date
2024-11-25
Date Accepted
Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that co-ordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffolding function mediates strong pro-survival signalling. Accordingly, cancer cells can hijack RIPK1’s scaffolding function to block necroptosis and evade immune detection. To overcome RIPK1’s pro-disease activity, I used a novel small-molecule proteolysis-targeting chimera (PROTAC), that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signalling hubs, accentuating the output of NF-kB, MAPK, and IRF>IFN signalling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. Consistently, RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy, by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, anti-tumour immunity and durable treatment responses. Consequently, PROTACs offer a promising approach to overcome radio- and/or immunotherapy resistance and enhance anti-cancer therapies.
Citation
2024
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Cell Death and Immunity