Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: GCJ-490A inhibited tumor growth by modulating the proportion of tumor-infiltrating immune cells.
Fig. 2: Immune cell infiltration and functional analysis following GCJ-490A treatment.
Fig. 3: GCJ-490A regulates TAMs polarization towards pro-inflammatory phenotype.
Fig. 4: Analysis of exhausted immune cell populations in different tumor models after GCJ-490A treatment.
Fig. 5: GCJ-490A combined with anti-PD-1 enhances T cell cytotoxicity and promotes the polarization of TAMs towards the anti-inflammatory M1 phenotype.
Fig. 6: GCJ-490A induces LL/2 cells to secrete CXCL7, which recruited MDSCs.

Similar content being viewed by others

References

  1. Hogg SJ, Beavis PA, Dawson MA, Johnstone RW. Targeting the epigenetic regulation of antitumour immunity. Nat Rev Drug Discov. 2020;19:776–800.

    Article  CAS  PubMed  Google Scholar 

  2. Shvedunova M, Akhtar A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat Rev Mol Cell Biol. 2022;23:329–49.

    Article  CAS  PubMed  Google Scholar 

  3. Zhao S, Allis CD, Wang GG. The language of chromatin modification in human cancers. Nat Rev Cancer. 2021;21:413–30.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Chun P. Histone deacetylase inhibitors in hematological malignancies and solid tumors. Arch Pharm Res. 2015;38:933–49.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao A, Zhou H, Yang J, Li M, Niu T. Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies. Signal Transduct Target Ther. 2023;8:71.

    Article  PubMed  PubMed Central  Google Scholar 

  6. McCaw TR, Li M, Starenki D, Liu M, Cooper SJ, Arend RC, et al. Histone deacetylase inhibition promotes intratumoral CD8+ T-cell responses, sensitizing murine breast tumors to anti-PD1. Cancer Immunol Immunother. 2019;68:2081–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lisiero DN, Soto H, Everson RG, Liau LM, Prins RM. The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells. J Immunother Cancer. 2014;2:8.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cao K, Wang G, Li W, Zhang L, Wang R, Huang Y, et al. Histone deacetylase inhibitors prevent activation-induced cell death and promote anti-tumor immunity. Oncogene. 2015;34:5960–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guerriero JL, Sotayo A, Ponichtera HE, Castrillon JA, Pourzia AL, Schad S, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages. Nature. 2017;543:428–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Huang J, Wang L, Dahiya S, Beier UH, Han R, Samanta A, et al. Histone/protein deacetylase 11 targeting promotes Foxp3+ Treg function. Sci Rep. 2017;7:8626.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Knox T, Sahakian E, Banik D, Hadley M, Palmer E, Noonepalle S, et al. Selective HDAC6 inhibitors improve anti-PD-1 immune checkpoint blockade therapy by decreasing the anti-inflammatory phenotype of macrophages and down-regulation of immunosuppressive proteins in tumor cells. Sci Rep. 2019;9:6136.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dahiya S, Beier UH, Wang L, Han R, Jiao J, Akimova T, et al. HDAC10 deletion promotes Foxp3+ T-regulatory cell function. Sci Rep. 2020;10:424.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang Y, Li X, Chen Q, Jiao F, Shi C, Pei M, et al. Histone deacetylase 6 regulates the activation of M1 macrophages by the glycolytic pathway during acute liver failure. J Inflamm Res. 2021;14:1473–85.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bejarano L, Jordāo MJC, Joyce JA. Therapeutic targeting of the tumor microenvironment. Cancer Discov. 2021;11:933–59.

    Article  CAS  PubMed  Google Scholar 

  15. Vizioli MG, Liu T, Miller KN, Robertson NA, Gilroy K, Lagnado AB, et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 2020;34:428–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Oh DY, Fong L. Cytotoxic CD4+ T cells in cancer: expanding the immune effector toolbox. Immunity. 2021;54:2701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gracia-Hernandez M, Yende AS, Gajendran N, Alahmadi Z, Li X, Munoz Z, et al. Targeting HDAC6 improves anti-CD47 immunotherapy. J Exp Clin Cancer Res. 2024;43:60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Orillion A, Hashimoto A, Damayanti N, Shen L, Adelaiye-Ogala R, Arisa S, et al. Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clin Cancer Res. 2017;23:5187–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Xie Z, Ago Y, Okada N, Tachibana M. Valproic acid attenuates immunosuppressive function of myeloid-derived suppressor cells. J Pharmacol Sci. 2018;137:359–65.

    Article  CAS  PubMed  Google Scholar 

  20. Liang R, Ding D, Li Y, Lan T, Ryabtseva S, Huang S, et al. HDACi combination therapy with IDO1i remodels the tumor microenvironment and boosts antitumor efficacy in colorectal cancer with microsatellite stability. J Nanobiotechnol. 2024;22:753.

    Article  CAS  Google Scholar 

  21. McCaw TR, Li M, Starenki D, Cooper SJ, Liu M, Meza-Perez S, et al. The expression of MHC class II molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth. Cancer Immunol Immunother. 2019;68:175–88.

    Article  CAS  PubMed  Google Scholar 

  22. Li X, Dai H, Wang H. Low-dose HDACi potentiates anti-tumor activity of macrophages in immunotherapy. Oncoimmunology. 2021;10:1935668.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hellmann MD, Jänne PA, Opyrchal M, Hafez N, Raez LE, Gabrilovich DI, et al. Entinostat plus pembrolizumab in patients with metastatic NSCLC previously treated with anti-PD-(L)1 therapy. Clin Cancer Res. 2021;27:1019–28.

    Article  CAS  PubMed  Google Scholar 

  24. Li Y, Seto E. HDACs and HDAC inhibitors in cancer development and therapy. Cold Spring Harb Perspect Med. 2016;6:a026831.

  25. Shi MQ, Xu Y, Fu X, Pan DS, Lu XP, Xiao Y, et al. Advances in targeting histone deacetylase for treatment of solid tumors. J Hematol Oncol. 2024;17:37.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang SW, Gong CJ, Su MB, Chen F, He T, Zhang YM, et al. Synthesis and in vitro and in vivo biological evaluation of tissue-specific bisthiazole histone deacetylase (HDAC) inhibitors. J Med Chem. 2020;63:804–15.

    Article  CAS  PubMed  Google Scholar 

  27. He T, Gao Y, Fang Y, Zhang Y, Zhang S, Nan F, et al. The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer. Cancer Biol Med. 2022;19:1172–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shen X, Zhou S, Yang Y, Hong T, Xiang Z, Zhao J, et al. TAM-targeted reeducation for enhanced cancer immunotherapy: mechanism and recent progress. Front Oncol. 2022;12:1034842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tafuri A, Shahinian A, Bladt F, Yoshinaga SK, Jordana M, Wakeham A, et al. ICOS is essential for effective T-helper-cell responses. Nature. 2001;409:105–9.

    Article  CAS  PubMed  Google Scholar 

  30. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537:417–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barry ST, Gabrilovich DI, Sansom OJ, Campbell AD, Morton JP. Therapeutic targeting of tumour myeloid cells. Nat Rev Cancer. 2023;23:216–37.

    Article  CAS  PubMed  Google Scholar 

  32. Jaillon S, Ponzetta A, Di Mitri D, Santoni A, Bonecchi R, Mantovani A. Neutrophil diversity and plasticity in tumour progression and therapy. Nat Rev Cancer. 2020;20:485–503.

    Article  CAS  PubMed  Google Scholar 

  33. Zebley CC, Zehn D, Gottschalk S, Chi H. T cell dysfunction and therapeutic intervention in cancer. Nat Immunol. 2024;25:1344–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Georgiev P, Muise ES, Linn DE, Hinton MC, Wang Y, Cai M, et al. Reverse translating molecular determinants of anti-programmed death 1 immunotherapy response in mouse syngeneic tumor models. Mol Cancer Ther. 2022;21:427–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Rivera LB, Meyronet D, Hervieu V, Frederick MJ, Bergsland E, Bergers G. Intratumoral myeloid cells regulate responsiveness and resistance to antiangiogenic therapy. Cell Rep. 2015;11:577–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kumar V, Donthireddy L, Marvel D, Condamine T, Wang F, Lavilla-Alonso S, et al. Cancer-associated fibroblasts neutralize the anti-tumor effect of CSF1 receptor blockade by inducing PMN-MDSC infiltration of tumors. Cancer Cell. 2017;32:654–668.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Loeuillard E, Yang J, Buckarma E, Wang J, Liu Y, Conboy C, et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma. J Clin Invest. 2020;130:5380–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Unver N. Identification of the dominant angiogenic CXCL class chemokines associated with non-small cell lung cancer via bioinformatics tools. Med Oncol. 2021;38:68.

    Article  CAS  PubMed  Google Scholar 

  39. Johnson ML, Strauss J, Patel MR, Garon EB, Eaton KD, Neskorik T, et al. Mocetinostat in combination with durvalumab for patients with advanced NSCLC: results from a phase I/II study. Clin Lung Cancer. 2023;24:218–27.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the Shanghai Municipal Science and Technology Commission “Shanghai Action Plan for Science, Technology and Innovation” in the field of experimental animal research project (21140902000, China), Program of Shanghai Academic/Technology Research Leader under the Science and Technology Innovation Action Plan (22XD1404400, China), Shandong Laboratory Program (SYS202205) and the Strategic Priority Research Program of the Chinese Academy of Science (XDB1060401).

Author information

Author notes

  1. These authors contributed equally: Wen-xin Zhang, Ting He

Authors and Affiliations

  1. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Wen-xin Zhang & Jian Ding

  2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Wen-xin Zhang, Jian Ding & Yan-fen Fang

  3. Division of Antitumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ting He, Kun Fang, Ying-lei Gao, Yi-ming Sun & Yi Chen

  4. University of Chinese Academy of Sciences, Beijing, 100049, China

    Ting He, Kun Fang, Fa-jun Nan, Jian Ding, Yi Chen & Yan-fen Fang

  5. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Fa-jun Nan, Jian Ding & Yi Chen

  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

    Fa-jun Nan

Authors
  1. Wen-xin Zhang
    View author publications

    Search author on:PubMed Google Scholar

  2. Ting He
    View author publications

    Search author on:PubMed Google Scholar

  3. Kun Fang
    View author publications

    Search author on:PubMed Google Scholar

  4. Ying-lei Gao
    View author publications

    Search author on:PubMed Google Scholar

  5. Yi-ming Sun
    View author publications

    Search author on:PubMed Google Scholar

  6. Fa-jun Nan
    View author publications

    Search author on:PubMed Google Scholar

  7. Jian Ding
    View author publications

    Search author on:PubMed Google Scholar

  8. Yi Chen
    View author publications

    Search author on:PubMed Google Scholar

  9. Yan-fen Fang
    View author publications

    Search author on:PubMed Google Scholar

Contributions

WXZ, YFF and YC designed the experiments. WXZ, TH, KF, YLG, YMS, FJN, JD, YFF and YC acquired the data. WXZ, YFF and YC drafted the manuscript. WXZ, TH, KF, YLG, YS, FJN, JD, YFF and YC and JD revised the manuscript. JD, YFF and YC obtained funding and supervised the study. All authors approved the final version of the paper.

Corresponding authors

Correspondence to Jian Ding, Yi Chen or Yan-fen Fang.

Ethics declarations

Competing interests

Jian Ding is the editor-in-chief of the journal and was not involved in the peer review or the decision making of the article. The authors declare no other competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Wx., He, T., Fang, K. 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 Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01646-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41401-025-01646-z

Keywords

This article is cited by

Search

Advanced search

Quick links