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

  • Acta Pharmacol Sin. 2025 Oct 1. doi: 10.1038/s41401-025-01646-z.
Wen-Xin Zhang  #  1  2 ,  Ting He  #  3  4 ,  Kun Fang  3  4 ,  Ying-Lei Gao  3 ,  Yi-Ming Sun  3 ,  Fa-Jun Nan  4  5  6 ,  Jian Ding  7  8  9  10 ,  Yi Chen  11  12  13 ,  Yan-Fen Fang  14  15
Affiliations
  • 1. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3. Division of Antitumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4. University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China.
  • 6. State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 7. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. [email protected].
  • 8. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 9. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 10. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. [email protected].
  • 11. Division of Antitumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 12. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • 13. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China. [email protected].
  • 14. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 15. University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 41034396 DOI: 10.1038/s41401-025-01646-z
Abstract

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.

Keywords
CXCL7; GCJ-490A; HDAC inhibitor; PD-1 antibody; tumor microenvironment.
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