ArticleBiomarker research2025
MORF4L2 induces immunosuppressive microenvironment and immunotherapy resistance through GRHL2/MORF4L2/H4K12Ac/CSF1 axis in triple-negative breast cancer.
Article in Biomarker research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- The neural stem cell‑NSCLC axis: Molecular drivers, microenvironment crosstalk and emerging therapies (Review).International journal of oncology · 2026Review
- CHST1 Drives Immunotherapy Resistance in Triple-Negative Breast Cancer by Orchestrating an Immunosuppressive Microenvironment via the NKRF-CCL20-Macrophage Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Construction of a Lysine Lactylation- and DNA Damage Repair-Related Gene Signature to Predict the Prognosis and Drug Sensitivity of Breast Cancer Patients.International journal of molecular sciences · 2026Article
- ANKFN1 in skin fibroblasts may modulate mast cell activity and is associated with dupilumab response in atopic dermatitis.Immunologic research · 2026Article
- Macrophages in obesity-related breast cancer: mechanistic insights and therapeutic opportunities.Breast cancer research : BCR · 2025Review
- Machine learning multiomics Deciphers GRHL2 associated tumor microenvironment evolution guiding precision therapeutics in breast cancer.Discover oncology · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
16 authors.
Funding
Abstract
backgroundAlthough immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed.
methodsIn this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out.
resultsMortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to the M2 phenotype. Furthermore, we revealed that grainyhead like transcription factor 2 (GRHL2) could promote MORF4L2 transcription by binding to the MORF4L2 enhancer region. Notably, BLZ549, an inhibitor of CSF1R, restored the anti-PD1 sensitivity by blocking the GRHL2/MORF4L2/H4K12Ac/CSF1 axis.
conclusionsGRHL2/MORF4L2/H4K12Ac/CSF1 axis plays an important role in anti-PD1 resistance. CSF1R inhibitors can reverse GRHL2/MORF4L2-mediated anti-PD1 resistance.
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