PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy

Lei Wang, Yufeng Xiao, Yuewan Luo, Rohan P. Master, Jiao Mo, Myung Chul Kim, Yi Liu, Chandra K. Maharjan, Urvi M. Patel, Umasankar De, Madison E. Carelock, Tanzia Islam Tithi, Xiangming Li, Donald R. Shaffer, Kevin R. Guertin, Haoyang Zhuang, Emily Moser, Keiran S.M. Smalley, Dongwen Lv, Daohong ZhouGuangrong Zheng, Weizhou Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04–mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Original languageEnglish (US)
Article numbere20231519
JournalJournal of Experimental Medicine
Volume221
Issue number3
DOIs
StatePublished - Mar 4 2024

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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