Abstract Cancer immunotherapies have achieved unprecedented clinical responses and are revolutionizing cancer treatments. Despite of the tremendous success of cancer immunotherapies, it remains unclear why only a subset of individuals responds to treatment and how to turn non-responders to become responsive. Receptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by tumor necrosis factor-α (TNF-α), toll-like receptor ligands, and interferons. In TNF-α signaling, the kinase activity of RIPK1 is required for inducing apoptosis and necroptosis. RIPK1 also serves as a kinase-independent scaffolding protein to recruit the NF-κB activation complex, leading to activation of the NF-κB pathway and cell survival. Interestingly, mice with a kinase-dead Ripk1 mutation (mimicking inhibitors) and with Ripk1 knockout (mimicking degraders) showed completely different phenotypes. Recently, our work, along with two other independent studies, showed that knockout of RIPK1 in cancer cells significantly sensitized tumors to anti-PD1, leading to favorable changes in the tumor microenvironment. Homozygous loss-of-function RIPK1 mutations are well tolerated in humans. Patients with complete loss of RIPK1 protein only showed symptoms confined to the immune system with primary immunodeficiency and/or intestinal inflammation, suggesting that pharmacological RIPK1 degradation can be potentially safe and tolerable, especially with transient intervention in clinical settings. Leveraging the Proteolysis targeting chimera (PROTAC) technology, we developed a first-in-class RIPK1 degrader LD4172. In our preliminary study, we showed that LD4172 potently degrades RIPK1 protein in a panel of human cancer cell lines and inhibits NF-κB activities. The degradation specificity of LD4172 was confirmed with proteomics profiling. In a mouse melanoma immunocompetent model, LD4172 significantly synergized with anti-PD1. In this project, we will continue our medicinal chemistry campaign to develop an orally available RIPK1 degrader and test its efficacy in a panel of preclinical models with different immune subtypes. Successful completion of this project will lead to the development of not only a chemical probe to interrogate RIPK1 related biology but also a highly promising therapeutic agent to advance cancer immunotherapies. We strive to use diverse preclinical models to test the RIPK1 degrader to identify biomarkers, which is very important to identify responsive patients in future clinical translations.