Entinostat induces antitumor immune responses through immune editing of tumor neoantigens
Open accessAbstract
Although immune-checkpoint inhibitors (ICIs) have been a remarkable advancement in bladder cancer treatment, the response rate to single-agent ICIs remains suboptimal. There has been substantial interest in the use of epigenetic agents to enhance ICI efficacy, although precisely how these agents potentiate ICI response has not been fully elucidated. We identified entinostat, a selective HDAC1/3 inhibitor, as a potent antitumor agent in our immune-competent bladder cancer mouse models (BBN963 and BBN966). We demonstrate that entinostat selectively promoted immune editing of tumor neoantigens, effectively remodeling the tumor immune microenvironment, resulting in a robust antitumor response that was cell autonomous, dependent upon antigen presentation, and associated with increased numbers of neoantigen-specific T cells. Finally, combination treatment with anti-PD-1 and entinostat led to complete responses and conferred long-term immunologic memory. Our work defines a tumor cell-autonomous mechanism of action for entinostat and a strong preclinical rationale for the combined use of entinostat and PD-1 blockade in bladder cancer.
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Several previous studies have demonstrated that inhibition of HDAC enzymes by less-selective compounds can lead to increases in antigen presentation, as well as changes to intratumoral T-cell populations.
“Several previous studies have demonstrated that inhibition of HDAC enzymes by less-selective compounds can lead to increases in antigen presentation, as well as changes to intratumoral T-cell populations (40–43).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes <i>STK11</i> -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [43]
The Introduction reports that HDAC inhibitors can alter the tumor immune microenvironment, and the paper reports antigen-presentation-dependent responses and changes in tumor T-cell populations. But those findings concern entinostat, which the Introduction and Methods describe as a selective HDAC1/3 inhibitor; this paper does not establish both effects for the less-selective compounds specified in the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHDAC inhibitor combined with α-PD-1/PD-L1 has shown a synergistic antitumor effect in murine tumor models.
“HDAC inhibitor combined with α-PD-1/PD-L1 has shown a synergistic antitumor effect in murine tumor models [329–331].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [330]
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“In the cancer-immunity cycle, HDAC inhibition enhances antigen presentation by increasing major histocompatibility complex (MHC) class I and II in Merkel cell carcinoma [12], bladder cancer [13], and NSCLC [14], resulting in the promotion of cytotoxic CD8+ T-cellmediated tumor cell killing.”
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“As expected, most DNA damage agents and well-studied immunoenhancing agents strongly induced the HRD-EXCUTE, including Entinostat, a highly selective histone deacetylase (HDAC1/3) inhibitor, inhibits the removal of the acetyl groups on histone and is typically related to transcriptional activity.[32] It was approved t…”
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Potential therapies targeting nuclear metabolic regulation in cancer
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Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer
Nunes, S. P., Morales, L., Rubio, C., Munera-Maravilla, E., Lodewijk, I., Suárez-Cabrera, C., Martínez, V. G., Pérez-Escavy, M., Pérez-Crespo, M., Sánchez, M. A., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-023-01786-3 · Cited by 14 · see citing works
“HDACi have been previously shown to modulate tumor microenvironment and improve response to ICI in BC and other cancer types [14 – 16].”
BackgroundMethodInfluentialTargeting intracellular proteins with cell type-specific functions for cancer immunotherapy
Carelock, M. E., Master, R. P., Kim, M., Jin, Z., Wang, L. A., Maharjan, C. K., Hua, N., De, U., Kolb, R. H., Xiao, Y., et al. (2023) · Life Medicine · doi:10.1093/lifemedi/lnad019 · Cited by 13 · see citing works
“The class I HDAC-specific inhibitor entinostat induces immune editing of tumor neoantigens, resulting in a strong anti-tumor immune response [127].”
Mechanistic insights into medulloblastoma relapse
Peterson, K. D., Turos‐Cabal, M., Salvador, A., Palomo-Caturla, I., Howell, A. J., Vieira, M. E., Greiner, S. M., Barnoud, T., & Rodríguez‐Blanco, J. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108673 · Cited by 16 · see citing works
Kelly, J. J., Bloodworth, N. C., Shao, Q., Shabanowitz, J., Hunt, D. F., Meiler, J., & Pires, M. M. (2024) · ACS Chemical Biology · doi:10.1021/acschembio.4c00312 · Cited by 12 · see citing works
Transcriptional repression by HDAC3 mediates T cell exclusion from Kras mutant lung tumors
McGuire, C. K., Meehan, A. S., Couser, E., Bull, L., Minor, A. C., Kuhlmann-Hogan, A., Kaech, S. M., Shaw, R. J., & Eichner, L. J. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2317694121 · Cited by 11 · see citing works
“Recent studies have identified that entinostat impacts the quantity of immunosuppressive myeloid - derived suppressor cells (MDSCs) in bladder ( 43 ), lung and renal ( 44 ), and breast ( 45 ) cancer models and that trametinib treatment can cause granulocytic MDSCs (gMDSCs) to block the function of…”
Fu, Z., Zhang, X., Gao, Y., Fan, J., & Gao, Q. (2023) · Clinical and Translational Medicine · doi:10.1002/ctm2.1320 · Cited by 11 · see citing works
The emerging role of histone deacetylase 1 in allergic diseases
Wang, Y., & Wang, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1027403 · Cited by 11 · see citing works
“Entinostat selectively promotes the immune editing of new tumor antigens, leading effectively reshaping the tumor immune microenvironment (55).”
BackgroundHan, R., Zhou, H., Peng, B., Yu, S., Zhu, J., & Chen, J. (2025) · Vaccines · doi:10.3390/vaccines13060550 · Cited by 10 · see citing works
“…cell populations, including Tregs and monocytic myeloid-derived suppressor cells (M-MDSCs), further potentiating anti-tumor immunity [133]. b. Combination of BN-Brachyury Vaccine, M7824, T-DM1, and Entinostat A multi-drug regimen combining BN-Brachyury vaccine, M7824 (a novel…”
Ahronian, L. G., Sahu, S., Zhang, M., Patel, A. S., Geng, K., Bhattacharya, R., Falchook, G. S., Goldman, J. W., Spira, A. I., Punekar, S. R., et al. (2025) · Cancer Research · doi:10.1158/0008-5472.can-25-0998 · Cited by 9 · see citing works
“Several previous studies have demonstrated that inhibition of HDAC enzymes by less-selective compounds can lead to increases in antigen presentation, as well as changes to intratumoral T-cell populations (40–43).”
HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden–induced T-cell Exhaustion
Nguyen, A., Brown, D., Krishnan, R., Bastin, D. J., Deng, L., Chen, L., Salem, O., Walsh, S. R., Bramson, J. L., & Wan, Y. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2181 · Cited by 8 · see citing works
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“The broad immunopotentiating effects of HDA-Cis include suppressing the infiltration of regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs); remodeling the tumor inflammatory landscape; and promoting tumor antigen cross-presentation [47–50].”
Fu, Z., Song, Y., Liu, F., Chen, L., Cai, S., Cui, P., Wang, G., Xie, W., Zhang, S., Ding, L., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.12.014 · Cited by 9 · see citing works
Identification of the Prognostic Biomarkers CBX6 and CBX7 in Bladder Cancer
Li, X., Li, L., Xiong, X., Kuang, Q., Peng, M., Zhu, K., & Luo, P. (2023) · Diagnostics · doi:10.3390/diagnostics13081393 · Cited by 8 · see citing works
“Multiple studies have shown that entinostat, a selective class I HDAC inhibitor, induces an anticancer response through immunological editing of tumor neoantigens and modification of the tumor immune microenvironment [10].”
BackgroundDiscovery of first novel sigma/HDACi dual-ligands with a potent in vitro antiproliferative activity
Barbaraci, C., di Giacomo, V., Maruca, A., Patamia, V., Rocca, R., Dichiara, M., Rienzo, A. D., Cacciatore, I., Cataldi, A., Balaha, M. F., et al. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106794 · Cited by 9 · see citing works
Holay, N., Somma, A. J., Duchow, M. W., Soleimani, M., Capasso, A., Kottapalli, S., Rios, J., Giri, U. P., Diamond, J. R., Schreiber, A., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1260545 · Cited by 8 · see citing works
“This includes altering expression of tumor antigens (12, 14, 15), upregulating antigen-presenting machinery (MHC-I/II) (16, 17), enhancing secretion of T cell-recruiting chemokines (4), rendering tumors susceptible to death receptor killing (12, 18), and altering the balance of suppressive and inflammatory myeloid cel…”
BackgroundSchlom, J., Donahue, R. N., Palena, C., Gameiro, S. R., Hodge, J. W., Hamilton, D. H., & Gulley, J. L. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009595 · Cited by 6 · see citing works
“12 In another study, 13 a neoepitope vaccine induced some anti-neoepitope T-cell responses, but failed to induce antitumor activity.”
Sekeres, M., Lengle, D., Abbey, L., Kassack, M. U., Fischer, F., Kurz, T., & Fritz, G. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2025.120018 · Cited by 6 · see citing works
The contributing factors of resistance or sensitivity to epigenetic drugs in the treatment of AML
Kelaye, S. K., Najafi, F., Kazemi, B., Foruzandeh, Z., Seif, F., Solali, S., & Alivand, M. R. (2022) · Clinical & Translational Oncology · doi:10.1007/s12094-022-02776-0 · Cited by 5 · see citing works
Histone deacetylase inhibitors as sanguine epitherapeutics against the deadliest lung cancer
Ganai, S. A., Shah, B. A., & Yatoo, M. A. (2023) · Advances in cancer research · doi:10.1016/bs.acr.2022.12.003 · Cited by 5 · see citing works
Drug Repurposing in Oncology: A Strategic Pathway to Unlocking New Therapeutic Potential
Shaik, R., Laddika, S. G., Unnisa, M., Hamza, A., Begum, S., & Sarwar, S. F. (2025) · Therapeutic Innovation & Regulatory Science · doi:10.1007/s43441-025-00895-8 · Cited by 4 · see citing works
Targeting the NAT10-HDAC4 positive feedback loop counteracts immunosuppression in breast cancer
Ma, X., Jin, S., Zhang, X., Zhao, L., Wang, H., Liu, S., Li, H., Wang, Q., Gao, S., Wang, J., et al. (2026) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-025-03638-7 · Cited by 4 · see citing works
“This observation is consistent with studies suggesting that Class I HDAC inhibitors, such as Entinostat, can enhance cytotoxic T lymphocyte activation, inhibit the immunosuppressive activities of Tregs and MDSCs, and reverse the immunosuppressive tumor microenvironment [61].”
Fisher, R. J., Park, K., Lee, K., Pinjušić, K., Vanasse, A. P., Ennis, C. S., Farokh, P., Ficarro, S. B., Marto, J. A., Jiang, H., et al. (2025) · JCI Insight · doi:10.1172/jci.insight.190287 · Cited by 3 · see citing works
“…MS-275 promotes induction of tumor immune editing of tumor neoantigens and tumor immune responses in combination with ICI with α PD-1 therapy in bladder cancer (75); however, the doses of MS-275 required to elicit these responses were significantly greater than those used for corin in this study.”
Pleural Mesothelioma: Treatable Traits of a Heterogeneous Disease
Bertuccio, F. R., Agustoni, F., Galli, G., Bortolotto, C., Saddi, J., Baietto, G., Baio, N., Montini, S., Putignano, P., D’Ambrosio, G., et al. (2023) · Cancers · doi:10.3390/cancers15245731 · Cited by 3 · see citing works
“According to recent evidence, entinostat may improve the effects of immune check-point inhibitors (ICIs) in models of bladder and breast cancer by influencing the tumor microenvironment or immune-editing tumor neoantigens [149,150].”
BackgroundGhafoor, A., Zhu, L., Ohler, Z. W., Meskini, R. E., Ying, H., Atkinson, D., Day, A., Pate, N., Bassel, L., Wang, W., et al. (2026) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-25-1077 · Cited by 2 · see citing works
Role of myeloid-derived suppressor cells in bladder cancer and targeted therapeutic strategies
Boillat, S., Goasmat, V., Derré, L., & Domingos‐Pereira, S. (2025) · Gene · doi:10.1016/j.gene.2025.149772 · Cited by 2 · see citing works
Bree, B. A. V., & Eichner, L. J. (2026) · Science Advances · doi:10.1126/sciadv.aee7295 · Cited by 2 · see citing works
“Combination treat-ment with anti–PD-1 and entinostat led to complete responses and conferred long-term immunologic memory, providing preclinical rationale for combined entinostat and PD-1 blockade in bladder cancer ( 143 ).”
Huang, X., Huang, J., Huang, Q., & Zhou, S. (2023) · Translational Cancer Research · doi:10.21037/tcr-23-147 · Cited by 2 · see citing works
“Furthermore, we found that the high-risk group was more sensitive to stromal-and immune-related drugs [BMS-345541 (45), XAV939 (46), leflunomide (47), entinostat (48)], which correlated with the stromal properties of the high-risk group.”
Torres, E. T. R., Danilova, L., Tandurella, J., Gonzalez, E., Baugh, A. G., Al-Zubeidy, B., Hopkins, A. C., Murray, J., Downs, M., Kagohara, L. T., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6580687/v1 · Cited by 2 · see citing works
“Additionally, our study's observation of increased clonal diversity in T cell receptor (TCR) repertoires after triplet treatment aligns with earlier reports suggesting that entinostat can enhance the effectiveness of ICIs by promoting a more diverse and robust T cell response 41 .”
Células troncales cancerígenas en carcinoma oral de células escamosas. Revisión de la literatura
Rodríguez-Vargas, M. P., Alvarado-Garnica, H., Gutiérrez-Verdín, L. D., Villanueva‐Sánchez, F. G., & García‐Contreras, R. (2022) · Revista Científica Odontológica · doi:10.21142/2523-2754-1002-2022-106 · Cited by 1 · see citing works
“La expresión de los genes suprimidos puede restablecerse mediante la inhibición de la actividad de la histona desacetilasa ( 26 ).”
BackgroundThe prognostic value and immunological role of SULF2 in adrenocortical carcinoma
Yan, J., Xie, X., Li, Q., Liang, P., Zhang, J., & Xu, G. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e13613 · Cited by 1 · see citing works
“Besides, PD1, an important immune checkpoint component, has been recognized as an important target for tumor immunotherapy [33,34].”
BackgroundTansou, R., Kubo, T., Nishida, H., Nishimura, Y., Mihara, K., Yanagihara, K., & Seyama, T. (2025) · Biomolecules · doi:10.3390/biom15020293 · Cited by 1 · see citing works
Smith, K. H., Trovillion, E. M., McKinney, K. Q., Gourabathini, P., Wells, K., Gandra, D., Sholler, C., Votruba, I., Oesterheld, J. E., & Sholler, G. L. S. (2025) · Cancers · doi:10.3390/cancers17244018 · Cited by 1 · see citing works
“Some examples of these specific HDAC inhibitors include romidepsin (class 1 HDACs), Ricolinostat (HDAC6), and Entinostat (HDAC 1&3) [25,26].”
Epigenetic remodeling in sarcoma promotes T-cell infiltration via modulation of the Hippo pathway
Santos, M. C. D. L., Chen, Y., Zárate, A. G. D., Sorteberg, A. L., Zhao, H., Vázquez-Cabrera, G., bigdeli, N., Kolbeinsdóttir, S., Mannion, A. J., Baldran-Groves, L., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-014601 · Cited by 1 · see citing works
The histone deacetylase family in health and disease
Wen, R., Yang, Y., Zhang, T., Zhang, S.-Y., Yang, X.-R., Zhang, L.-Y., Hao, P.-H., Zheng, Y., Ni, Y., & Zhang, T. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02764-8 · Cited by 1 · see citing works
“273 In summary, most current fi ndings suggest that HDACs drive gynecologic tumor progression by in fl uencing apoptosis, proliferation and immune responses.”
A multispecies framework for modeling adaptive immunity and immunotherapy in cancer
Qi, T., Vincent, B. G., & Cao, Y. (2023) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1010976 · Cited by 1 · see citing works
“Thirty-four 2 neoantigens putatively expressed by the cells were identified and tested for immunogenicity ex 3 vivo [28] (see Methods).”
BackgroundSelf-citationZheng, S., Barczak, W., Liu, G., & Thangue, N. B. L. (2024) · Royal Society of Chemistry eBooks · doi:10.1039/9781837674916-00228 · Cited by 1 · see citing works
Impact of Post-Translational Modification on MHC Peptide Binding and TCR EngagementPreprint
Kelly, J. J., Bloodworth, N. C., Shao, Q., Shabanowitz, J., Hunt, D. F., Meiler, J., & Pires, M. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.02.530810
“To this end, there are a high number of ongoing studies evaluating the combination of KDAC inhibitors and PD-1/PDL-1 inhibitors across many types of difficult-to-treat tumors.(89-95) We are currently working towards using our platform to demonstrate how KDAC inhibitors directly lead to an immunopeptidome that reveal c…”
BackgroundTorres, E. T. R., & Connolly, R. M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-91367-6.00015-5
Göv, E., & Bayrak, G. K. (2024) · Journal of Scientific Reports-A · doi:10.59313/jsr-a.1397224
Patel, A. A., Alothaid, H., Mallick, A. K., Alalawy, A. I., Mirdad, R. T., Mirdad, M. T., Mirdad, M. T., Ahsan, M., & Tarique, M. (2024) · Indian Journal of Pharmaceutical Education and Research · doi:10.5530/ijper.58.3.88
“33-35 The ΔG value for the interaction between entinostat and the HDAC2 binding pocket was determined to be -8.5 kcal/mol.”
BackgroundInfluentialDrug Discovery for Chromatin Readers, Writers, Erasers, Remodelers and Epitranscriptomic Targets
(2024) · Royal Society of Chemistry eBooks · doi:10.1039/9781837674916-part3
The Emerging Landscape of Mouse Bladder Cancer Models
Iwata, T., & Yousef, A. R. E. (2024) · Springer eBooks · doi:10.1007/978-3-031-68505-7_16
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Johnson, K., Lim, J. J., WU, W., Tu, N., & Zhang, S. X. (2026) · Research Square · doi:10.21203/rs.3.rs-9890379/v1
“These findings are consistent with previous reports indicating that HDAC inhibitors can remodel the tumor microenvironment and enhance T-cell functionality without necessarily increasing T-cell numbers (20).”
InfluentialTo, K. K. W., Ma, T., Wang, L., & Cho, W. C. S. (2026) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2026.2747520
- Authors
- Truong, A. S., Zhou, M., Krishnan, B., Utsumi, T., Manocha, U., Stewart, K. G., Beck, W., Rose, T. L., Milowsky, M. I., He, X., Smith, C. C., Bixby, L. M., Perou, C. M., Wobker, S. E., Bailey, S. T., Vincent, B. G., & Kim, W. Y.
- Affiliations
- UNC Lineberger Comprehensive Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Vincent, Benjamin G.
- Kim, William Y.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2021-08-16
- Volume
- 131
- Issue
- 16
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC8363284
- OpenAlex
- W3195143313
- Cited by
- 84
- References
- 40
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 19 · 2023: 27 · 2022: 14 · 2021: 1
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- American Cancer Society (RSG-14-219-01-TBG)
- University Cancer Research Fund (N/A)
- Uhera Foundation (N/A)
- National Cancer Institute (F31 CA247250, K12CA120780, R01-CA241810)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Surgery › Bladder and Urothelial Cancer Treatments
- Keywords
- entinostat, histone deacetylase inhibitors, bladder cancer, neoantigens, immunoediting, antitumor immunity, tumor immune microenvironment, antigen presentation, anti-PD-1 therapy, combination immunotherapy, immunological memory, cell-autonomous mechanisms
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Antigens, Neoplasm, Benzamides, Urinary Bladder Neoplasms, Humans, Immunity, Immunocompetence, Immunotherapy, Mice, Inbred C57BL, Pyridines, T-Lymphocytes, Mice, SCID, Mice, Inbred NOD, Mice, Knockout, Cell Line, Tumor, Mice, Histone Deacetylase Inhibitors, Tumor Microenvironment
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