HDAC6 facilitates LUAD progression by inducing EMT and enhancing macrophage polarization towards the M2 phenotype

Histone deacetylase 6 (HDAC6) plays a critical role in lung adenocarcinoma (LUAD) prognosis and the tumor immune microenvironment (TIME). This study, utilizing public datasets and experimental validation, revealed that HDAC6 is upregulated in LUAD, correlating with poor survival outcomes and an immunosuppressive TIME characterized by increased Tregs, CAFs, M2 macrophages, and MDSCs. HDAC6-high patients showed reduced immunotherapy response. HDAC6 knockout inhibited tumor growth, suppressed PI3K/AKT/mTOR signaling and EMT, and enhanced apoptosis and M1 macrophage recruitment. HDAC6 inhibition synergized with anti-PD-1 therapy, suggesting a potential combinatorial strategy for LUAD treatment. HDAC6 serves as a key prognostic marker and therapeutic target in LUAD.

• Publication year

  2025

• Venue

  npj Precision Oncology

• Publication date

  2025-05-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41698-025-00949-yPMID 40404897PMCID 12098887
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Combined anti-PD-1, HDAC inhibitor and anti-VEGF for MSS/pMMR colorectal cancer: a randomized phase 2 trial

  2024cited by this paper
• RRM2 Is a Putative Biomarker and Promotes Bladder Cancer Progression via PI3K/AKT/mTOR Pathway

  2024cited by this paper
• High tumor mutational burden assessed through next-generation sequencing predicts favorable survival in microsatellite stable metastatic colon cancer patients

  2024cited by this paper
• The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy

  2024cited by this paper
• Oxidative phosphorylation related gene COA6 is a novel indicator for the prognosis and immune response in lung adenocarcinoma

  2024cited by this paper
• Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial

  2024cited by this paper
• Dual molecule targeting HDAC6 leads to intratumoral CD4+ cytotoxic lymphocytes recruitment through MHC-II upregulation on lung cancer cells

  2024cited by this paper
• Prognostic and immunological characteristics of CDK1 in lung adenocarcinoma: A systematic analysis

  2023cited by this paper
• Analysis and Visualization of Longitudinal Genomic and Clinical Data from the AACR Project GENIE Biopharma Collaborative in cBioPortal

  2023cited by this paper
• Inhibition of histone deacetylase 6 destabilizes ERK phosphorylation and suppresses cancer proliferation via modulation of the tubulin acetylation-GRP78 interaction

  2023cited by this paper
• Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer.

  2022cited by this paper
• GSCA: an integrated platform for gene set cancer analysis at genomic, pharmacogenomic and immunogenomic levels

  2022cited by this paper
• HDAC6-dependent deacetylation of TAK1 enhances sIL-6R release to promote macrophage M2 polarization in colon cancer

  2022cited by this paper
• HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis.

  2022cited by this paper
• HDAC6: A unique HDAC family member as a cancer target

  2022cited by this paper
• Sangerbox: A comprehensive, interaction‐friendly clinical bioinformatics analysis platform

  2022cited by this paper
• Characterization of Somatic Mutations That Affect Neoantigens in Non-Small Cell Lung Cancer

  2022cited by this paper
• Coupling the immunomodulatory properties of the HDAC6 inhibitor ACY241 with Oxaliplatin promotes robust anti-tumor response in non-small cell lung cancer

  2022cited by this paper
• Design, synthesis and biological evaluation of 3, 4-disubstituted-imidazolidine-2, 5-dione derivatives as HDAC6 selective inhibitors.

  2021cited by this paper
• Preclinical Development and First-in-Human Study of KA2507, a Selective and Potent Inhibitor of Histone Deacetylase 6, for Patients with Refractory Solid Tumors

  2021cited by this paper
• Histone deacetylase 6-mediated downregulation of TMEM100 expedites the development and progression of non-small cell lung cancer

  2021cited by this paper
• Author Correction: Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer

  2021cited by this paper
• HDAC6, modulated by miR-206, promotes endometrial cancer progression through the PTEN/AKT/mTOR pathway

  2020cited by this paper
• Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma

  2020cited by this paper
• HDAC6 ZnF UBP as the Modifier of Tau Structure and Function.

  2020cited by this paper
• HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer

  2020cited by this paper
• Histone Deacetylase Inhibitors to Overcome Resistance to Targeted and Immuno Therapy in Metastatic Melanoma

  2020cited by this paper
• The USP10-HDAC6 axis confers cisplatin resistance in non-small cell lung cancer lacking wild-type p53

  2020cited by this paper
• Histone Deacetylase Inhibition with Panobinostat Combined with Intensive Induction Chemotherapy in Older Patients with Acute Myeloid Leukemia: Phase I Study Results

  2019cited by this paper
• Cancer statistics, 2019

  2019cited by this paper
• Inhibition of HDAC6 Attenuates Tumor Growth of Non-Small Cell Lung Cancer

  2019cited by this paper
• Author Correction: 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

  2019cited by this paper
• The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy

  2019cited by this paper
• HDAC6 serves as a biomarker for the prognosis of patients with renal cell carcinoma

  2017cited by this paper
• The immunohistochemical expression and potential prognostic value of HDAC6 and AR in invasive breast cancer.

  2017cited by this paper
• Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: a multicentre phase 1b trial.

  2016cited by this paper
• HDACs and HDAC Inhibitors in Cancer Development and Therapy.

  2016cited by this paper
• Targeting histone deacetylase 6 mediates a dual anti‐melanoma effect: Enhanced antitumor immunity and impaired cell proliferation

  2015cited by this paper
• Oncogenic Shp2 disturbs microtubule regulation to cause HDAC6-dependent ERK hyperactivation

  2014cited by this paper
• Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

  2013cited by this paper
• Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer

  2013cited by this paper
• The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.

  2012cited by this paper
• Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

  2012cited by this paper

• Role of HDAC6 in carcinomas

  2026cites this paper
• HDAC6 orchestrates metastatic and immunosuppressive programs in small cell lung cancer through S100A2-TGF-β/SMAD and CSF1R signaling

  2026influential citation
• The regulatory mechanisms and treatment of HDAC6 in immune dysregulation diseases

  2025cites this paper
• Chidamide suppresses macrophage-mediated immune evasion and tumor progression in small cell lung cancer by targeting the STAT4/CCL2 signaling pathway

  2025cites this paper
• Histone deacetylase 6 modulates autophagy through HIF-1α/BNIP3 signaling in lung cancer.

  2025cites this paper
• The Leupaxin/HDAC6/EGR2 axis facilitates breast cancer progression by enhancing macrophage M2 polarization

  2025cites this paper