{Reference Type}: Journal Article
{Title}: A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.
{Author}: Mannion J;Gifford V;Bellenie B;Fernando W;Ramos Garcia L;Wilson R;John SW;Udainiya S;Patin EC;Tiu C;Smith A;Goicoechea M;Craxton A;Moraes de Vasconcelos N;Guppy N;Cheung KJ;Cundy NJ;Pierrat O;Brennan A;Roumeliotis TI;Benstead-Hume G;Alexander J;Muirhead G;Layzell S;Lyu W;Roulstone V;Allen M;Baldock H;Legrand A;Gabel F;Serrano-Aparicio N;Starling C;Guo H;Upton J;Gyrd-Hansen M;MacFarlane M;Seddon B;Raynaud F;Roxanis I;Harrington K;Haider S;Choudhary JS;Hoelder S;Tenev T;Meier P;
{Journal}: Immunity
{Volume}: 57
{Issue}: 7
{Year}: 2024 Jul 9
{Factor}: 43.474
{DOI}: 10.1016/j.immuni.2024.04.025
{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.