ArticleJournal of experimental & clinical cancer research : CR2025
CD47 blockade reverses resistance to HDAC inhibitor by liberating anti-tumor capacity of macrophages.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed.
- Tissue-Resident Macrophage in Inflammation and Cancer.MedComm · 2026Review
- Piroctone olamine promotes BECN1 transcription and activates autophagy by targeting HDAC6 in colorectal cancer.Acta pharmacologica Sinica · 2026Article
- Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.Discover oncology · 2026Article
- Targeting circSFPQ_008/SFPQ/BRCA1 axis for overcoming platinum resistance in ovarian cancer.MedScience · 2026Article
- Epigenetic programming of macrophages across inflammatory and malignant diseases.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- Post-translational modifications of immune checkpoints: molecular mechanisms, tumor microenvironment remodeling, and therapeutic implications.Journal of biomedical science · 2026Review
- Decoding macrophage heterogeneity in the pulmonary fibrosis lung cancer transition.Frontiers in immunology · 2026Review
- HDAC inhibitors in cancer therapy: sensitization mechanisms, combination strategies, and translational challenges.Frontiers in cell and developmental biology · 2026Review
- Targeting CD47-mediated cancer senescence, a novel strategy for cancer immunotherapy.Frontiers in immunology · 2026Review
- CLEVER-1Frontiers in immunology · 2026Review
- Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.Frontiers in immunology · 2026Review
- Engineered macrophages accumulate in solid tumors and locally deliver immune-activating proteins to inhibit tumor progression.Translational cancer research · 2025Article
- Non-Histone Lysine Modifications in Tumor Microenvironment: Mechanisms and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases.International journal of molecular sciences · 2025Review
- PYGO1 drives gastric cancer progression via the ITGB1/CD47 axis and is therapeutically targeted by pentagalloylglucose.Journal of translational medicine · 2025Article
- The hydroxamate based HDAC inhibitor WMJ-J-09 induces colorectal cancer cell death by targeting tubulin and downregulating survivin.Scientific reports · 2025Article
Corrections and comments
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19 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTargeting oncogenic histone modification by histone deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how HDACi influences the tumor microenvironment, in order to identify potential targets for reversing the resistance to HDACi therapies.
methodsMacrophage infiltration was compared between HDACi-responding and HDACi-nonresponding cancer patients. The impact of HDACis on the phagocytic capacity of macrophages was investigated through macrophage-tumor cell co-culture system. CD47 expression in tumor cell lines and patient-derived organoids was evaluated by quantitative polymerase chain reaction (QPCR) and flow cytometry. Mechanistic studies were conducted through co-immunoprecipitation (co-IP) and chromatin immunoprecipitation (ChIP). The synergistic effect of HDACis and CD47 neutralizing antibody was assessed in subcutaneous murine tumor models. Bioinformatics approaches were adopted to analyze how macrophage infiltration determines the prognostic significance of CD47 expression in cancer patients.
resultsHigh macrophage infiltration is a determinant of therapeutic non-response to HDACi, cancer patients who did not respond to HDACi exhibit massive infiltration of tumor-associated macrophages (TAMs). TAM depletion reversed the resistance to HDACi therapy. Mechanistically, HDACi impaired the phagocytic capacity of macrophages against tumor cells through epigenetically upregulating CD47 expression. Reciprocally, HDACi-upregulated CD47 polarized macrophages towards a pro-tumor M2 phenotype through SIRPα ligation. In tumor-bearing mice, HDACi monotherapy only marginally delayed tumor progression, while the concurrent neutralization of CD47 exhibited potent anti-tumor effect through re-educating TAMs towards a tumoricidal phenotype. In cancer patients, CD47 was found to determine the prognostic significance of TAMs.
conclusionsOur study offers a rationale for targeting macrophage infiltration or blocking CD47 to sensitize HDACi therapies in cancer patients.
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