TY - JOUR
T1 - PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy
AU - Wang, Lei
AU - Xiao, Yufeng
AU - Luo, Yuewan
AU - Master, Rohan P.
AU - Mo, Jiao
AU - Kim, Myung Chul
AU - Liu, Yi
AU - Maharjan, Chandra K.
AU - Patel, Urvi M.
AU - De, Umasankar
AU - Carelock, Madison E.
AU - Tithi, Tanzia Islam
AU - Li, Xiangming
AU - Shaffer, Donald R.
AU - Guertin, Kevin R.
AU - Zhuang, Haoyang
AU - Moser, Emily
AU - Smalley, Keiran S.M.
AU - Lv, Dongwen
AU - Zhou, Daohong
AU - Zheng, Guangrong
AU - Zhang, Weizhou
N1 - Publisher Copyright:
© 2024 Wang et al.
PY - 2024/3/4
Y1 - 2024/3/4
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20231519
DO - 10.1084/jem.20231519
M3 - Article
C2 - 38334978
AN - SCOPUS:85184738954
SN - 0022-1007
VL - 221
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
M1 - e20231519
ER -