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To address the challenge posed by a poorly defined binding pocket within the intermediate domain\u00a0of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology\u00a0to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL\/6J mice. This work reports a RIPK1 degrader that serves as a chemical probe for investigating the scaffolding functions of RIPK1 and as a potential therapeutic agent to enhance tumor responses to ICBs therapy.<\/jats:p>","DOI":"10.1038\/s41467-024-55006-2","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T05:05:35Z","timestamp":1734325535000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Development of a RIPK1 degrader to enhance antitumor immunity"],"prefix":"10.1038","volume":"15","author":[{"given":"Xin","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rishi Ram","family":"Paudel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-5616","authenticated-orcid":false,"given":"Hanfeng","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan L.","family":"Holloman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Longyong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5365-9445","authenticated-orcid":false,"given":"Lang","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-6240","authenticated-orcid":false,"given":"Weiyi","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5898-6007","authenticated-orcid":false,"given":"Meng C.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-6202","authenticated-orcid":false,"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3625-7919","authenticated-orcid":false,"given":"Jin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,16]]},"reference":[{"key":"55006_CR1","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/s41573-021-00345-8","volume":"21","author":"AJ Korman","year":"2022","unstructured":"Korman, A. J., Garrett-Thomson, S. C. & Lonberg, N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat. Rev. Drug Discov. 21, 509\u2013528 (2022).","journal-title":"Nat. Rev. Drug Discov."},{"key":"55006_CR2","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1146\/annurev-immunol-070621-030155","volume":"40","author":"MD Vesely","year":"2022","unstructured":"Vesely, M. D., Zhang, T. & Chen, L. Resistance mechanisms to anti-PD cancer immunotherapy. Annu. Rev. Immunol. 40, 45\u201374 (2022).","journal-title":"Annu. Rev. Immunol."},{"key":"55006_CR3","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1038\/d41573-022-00030-4","volume":"21","author":"S Upadhaya","year":"2022","unstructured":"Upadhaya, S., Neftelinov, S. T., Hodge, J. & Campbell, J. Challenges and opportunities in the PD1\/PDL1 inhibitor clinical trial landscape. Nat. Rev. Drug Discov. 21, 482\u2013483 (2022).","journal-title":"Nat. Rev. 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Integrating genome-wide CRISPR immune screen with multi-omic clinical data reveals distinct classes of tumor intrinsic immune regulators. J. Immunother. Cancer 9, e001819 (2021).","journal-title":"J. Immunother. Cancer"},{"key":"55006_CR7","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nature23270","volume":"547","author":"RT Manguso","year":"2017","unstructured":"Manguso, R. T. et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 547, 413\u2013418 (2017).","journal-title":"Nature"},{"key":"55006_CR8","doi-asserted-by":"publisher","first-page":"14971","DOI":"10.1021\/acs.jmedchem.2c01518","volume":"65","author":"K Shi","year":"2022","unstructured":"Shi, K., Zhang, J., Zhou, E., Wang, J. & Wang, Y. Small-molecule receptor-interacting protein 1 (RIP1) inhibitors as therapeutic agents for multifaceted diseases: current medicinal chemistry insights and emerging opportunities. J. Med. 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X.Y., D.L., and J.W. are inventors on a patent covering RIPK1 degraders reported in this work, titled \u201cNovel RIPK1 Kinase-Targeting PROTACs and Methods of Use Thereof\u201d, with the identification number WO2022120118A1. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10683"}}