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HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models

文献类型：期刊论文

作者Zhang, Wen-xin2,3; He, Ting4,5; Fang, Kun4,5; Gao, Ying-lei4; Sun, Yi-ming4; Nan, Fa-jun1,5,6; Ding, Jian1,2,3,5; Chen, Yi1,4,5; Fang, Yan-fen3,5
刊名ACTA PHARMACOLOGICA SINICA
出版日期2025-10-01
页码13
关键词HDAC inhibitor GCJ-490A tumor microenvironment PD-1 antibody CXCL7
ISSN号1671-4083
DOI10.1038/s41401-025-01646-z
英文摘要Histone deacetylases (HDAC) inhibition represents one of the few validated strategies in epigenetic cancer therapies, demonstrating significant clinical efficacy in T-cell lymphomas and multiple myeloma, yet exhibiting limited efficacy against solid tumors. GCJ-490A is a novel HDAC inhibitor discovered by medicinal chemists in our institute, which exhibits potent in vitro and in vivo anticancer activity. In this study, we investigated the effects of GCJ-490A on the tumor microenvironment and its potential in synergy with PD-1 antibody in anti-tumor therapy. In syngeneic murine models of breast (EMT6) and lung (LL/2) cancers, we demonstrated that GCJ-490A alone and in combination with PD-1 antibody inhibited tumor growth by regulating T cells and tumor-associated macrophages (TAMs). Specifically, GCJ-490A significantly enhanced T-cell proliferation and cytotoxicity, evidenced by the increased expression of Ki67, CD107a and Granzyme B, and modulated TAMs towards a pro-inflammatory M1 phenotype, while reducing the M2 population. In addition, GCJ-490A upregulated PD-1 on T cells and PD-L1 on myeloid-derived suppressor cells (MDSCs) and TAMs, potentially enhancing PD-1 blockade efficacy. However, the anti-tumor efficacy was less pronounced in LL/2 tumors than in EMT6 tumors, which might be related to the increased infiltration of MDSCs in LL/2 tumors. GCJ-490A promoted MDSCs migration into the tumor by promoting the secretion of CXCL7 from LL/2 cells. In conclusion, GCJ-490A exerts its anti-tumor efficacy by reprogramming the tumor immune microenvironment in EMT6 and LL/2 tumor models, which is augmented when combined with anti-PD-1. However, CXCL7-mediated tumor-type-dependent recruitment of MDSCs by GCJ-490A may limit its therapeutic efficacy, and inhibition of the CXCL7/CXCR1/2 pathway might offer new strategies to address this challenge.
WOS关键词HISTONE DEACETYLASE INHIBITORS ; T-CELLS ; ANTITUMOR ; ACTIVATION
资助项目Shanghai Municipal Science and Technology Commission Shanghai Action Plan for Science, Technology and Innovation in the field of experimental animal research project[21140902000] ; Program of Shanghai Academic/Technology Research Leader under the Science and Technology Innovation Action Plan[22XD1404400] ; Shandong Laboratory Program[SYS202205] ; Strategic Priority Research Program of the Chinese Academy of Science[XDB1060401]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001585051700001
出版者NATURE PUBL GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/321555]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Ding, Jian; Chen, Yi; Fang, Yan-fen
作者单位1.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China
5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
6.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Wen-xin,He, Ting,Fang, Kun,et al. HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models[J]. ACTA PHARMACOLOGICA SINICA,2025:13.
APA Zhang, Wen-xin.,He, Ting.,Fang, Kun.,Gao, Ying-lei.,Sun, Yi-ming.,...&Fang, Yan-fen.(2025).HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models.ACTA PHARMACOLOGICA SINICA,13.
MLA Zhang, Wen-xin,et al."HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models".ACTA PHARMACOLOGICA SINICA (2025):13.

入库方式： OAI收割

来源：上海药物研究所

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