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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. [Display omitted] • RIPK1's scaffolding function protects cancer cells from immune detection and death • RIPK1-specific PROTAC degraders enhance innate immune signaling and necroptosis • RIPK1 PROTACs boost the immunostimulatory and antitumor effects of RT and ICB • PROTAC-mediated RIPK1 depletion suppresses skin inflammation Tumor cells frequently hijack RIPK1's scaffolding function to resist cell death and avoid immune detection. Mannion et al. describe the development of a RIPK1-selective PROTAC degrader that boosts the immunostimulatory and antitumor activity of radiotherapy (RT) and immune checkpoint blockade (ICB), heating up tumors and driving long-lasting antitumor immunity. [ABSTRACT FROM AUTHOR]