ArticleJournal for immunotherapy of cancer2025
METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Before the seeds arrive: pre-metastatic niche orchestration in bladder cancer.Cancer metastasis reviews · 2026Review
- Molecular functions, cellular responses and pathological implications of the RNA modification NNature reviews. Molecular cell biology · 2026Review
- Tumor-intrinsic NSUN2 orchestrates immunosuppression in lung adenocarcinoma via the mExperimental hematology & oncology · 2026Article
- MKRN2-Mediated Degradation of IGF2BP3 Suppresses MYC and Enhances CDK4/6 Inhibitor Sensitivity in Bladder Cancer.Cancers · 2026Article
- Myeloid-Derived Suppressor Cells: Function, Migration, and Therapeutic Opportunities in Glioblastoma.Cells · 2026Review
- Targeting mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- RNA Regulatory Networks: Key Hubs in the Panorama of Cancer and Emerging Therapeutic Targets.MedComm · 2026Review
- Ferroptosis-autophagy crosstalk in bladder cancer: mechanisms and therapeutic implications.Molecular cancer · 2026Review
- m6A methylation-modified ETV1 drives multiple myeloma progression and M2 polarization of tumor-associated macrophage through transcriptional activation of RBMS1.Journal of translational medicine · 2026Article
- Targeting epigenetic methylation: emerging diagnosis and therapeutic strategies in cancer.Experimental hematology & oncology · 2026Review
- Thymosin α1 combined with immune checkpoint inhibitors: synergistic remodeling of the tumor immune microenvironment to enhance clinical efficacy and safety.Frontiers in immunology · 2026Review
- Integrative Single-Cell Transcriptomics and Network Pharmacology Analysis of Xiao Qing Long Tang in Pediatric Cough-Variant Asthma.International journal of genomics · 2026Article
- RNA methylation in urological cancers: regulatory logic, biological functions, and clinical relevance.Frontiers in immunology · 2026Review
- RNA modifications: roles in immune cell biology and tumor regulation.Cancer cell international · 2025Review
- Epigenetic modifier m⁶A methylation: insights into the pathogenesis and therapeutic potential of autoimmune diseases.Journal of translational medicine · 2025Review
- Innovative Peptide Therapeutics in the Pipeline: Transforming Cancer Detection and Treatment.International journal of molecular sciences · 2025Review
- Correspondence on "METTL3 promotes an immunosuppressive microenvironment in bladder cancer via m6A-dependent CXCL5/CCL5 regulation" by TongJournal for immunotherapy of cancer · 2025Article
- The impact of METTL3 on bladder cancer through mFrontiers in oncology · 2025Review
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundBladder cancer (BLCA) is a challenging malignancy with a poor prognosis, particularly in muscle-invasive cases. Despite recent advancements in immunotherapy, response rates remain suboptimal. This study investigates the role of METTL3, an m6A RNA methylation "writer," in regulating the immune microenvironment of BLCA.
methodsThrough bioinformatics analysis, we identified METTL3 as being associated with the formation of an immunosuppressive microenvironment in BLCA and poor response to immunotherapy. Subsequently, we silenced METTL3 expression in BLCA cells using short hairpin RNA (shRNA) or inhibited its function with STM2457. The effectiveness of these interventions in remodeling the BLCA tumor microenvironment (TME) was confirmed through animal experiments and flow cytometry. Mechanistically, RNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing revealed the molecular pathways by which METTL3 regulates the TME. This was further validated using in vitro cell co-culture, immunoprecipitation, ELISA, and RNA degradation assays. The synergistic effect of METTL3 with anti-Programmed Cell Death Protein 1 (PD-1) treatment in BLCA was confirmed in both orthotopic and ectopic BLCA animal models.
resultsMETTL3 was found to increase CXCL5 levels and suppress CCL5 expression in an m6A-dependent manner, leading to increased recruitment of myeloid-derived suppressor cells (MDSCs) and reduced infiltration of CD8+T cells. Silencing METTL3 or inhibiting its function restored immune cell balance and significantly enhanced the efficacy of anti-PD-1 therapy. Clinically, METTL3 overexpression correlated with poor complete response rate to immune checkpoint inhibitors (ICIs) therapy, associated with an immunosuppressive microenvironment characterized by elevated MDSC levels and reduced CD8+T cell infiltration.
conclusionsThese findings highlight METTL3 as a key regulator of the immune microenvironment in BLCA and a promising therapeutic target to improve immunotherapy outcomes. Targeting METTL3 could potentially enhance the efficacy of ICIs in patients with BLCA.
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