{"doi":"10.1101/2023.08.09.552650","title":"Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy","abstract":"Abstract An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo , exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti- cancer immune responses and offers a new avenue for treating various types of cancer.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":410311,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9593,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":271117,"name":"Yufeng Xiao","orcid":"0000-0002-2679-0800","position":1,"is_corresponding":false},{"id":677200,"name":"Yuewan Luo","orcid":"0000-0002-8964-5301","position":2,"is_corresponding":false},{"id":872688,"name":"Rohan Master","orcid":"0009-0005-7474-2941","position":3,"is_corresponding":false},{"id":677202,"name":"Jiao Mo","orcid":"0009-0002-1721-9781","position":4,"is_corresponding":false},{"id":630998,"name":"Myung‐Chul Kim","orcid":"0000-0003-3389-1244","position":5,"is_corresponding":false},{"id":1190375,"name":"Yi Liu","orcid":"0000-0003-0548-6073","position":6,"is_corresponding":false},{"id":1190665,"name":"Urvi M. Patel","orcid":null,"position":7,"is_corresponding":false},{"id":1190376,"name":"Xiangming Li","orcid":"0000-0002-8795-6560","position":8,"is_corresponding":false},{"id":1190377,"name":"Donald R. Shaffer","orcid":"0000-0003-4668-5810","position":9,"is_corresponding":false},{"id":764371,"name":"Kevin R. Guertin","orcid":"0009-0002-2462-0784","position":10,"is_corresponding":false},{"id":762443,"name":"Emily K. Moser","orcid":"0000-0001-6386-5894","position":11,"is_corresponding":false},{"id":325110,"name":"Keiran S.M. Smalley","orcid":"0000-0003-1089-9307","position":12,"is_corresponding":false},{"id":237881,"name":"Daohong Zhou","orcid":"0000-0002-2400-6461","position":13,"is_corresponding":false},{"id":237880,"name":"Guangrong Zheng","orcid":"0000-0002-8106-6663","position":14,"is_corresponding":false},{"id":273483,"name":"Weizhou Zhang","orcid":"0000-0002-8236-0346","position":15,"is_corresponding":false},{"id":703738,"name":"Lei Wang","orcid":"0000-0003-3549-4306","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T01:21:35.071397Z","pmid":"37609171","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}