ArticleCell death and differentiation2023
METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer.
Article in Cell death and differentiation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 65 papers, 1 of them a synthesis that pooled it.
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Who cites it
65 citing papers in PubMed, 1 synthesis or guideline pooled it, 77 citations in OpenAlex.
- Emerging insights into thyroid cancer from immunotherapy perspective: A bibliometric analysis.Human vaccines & immunotherapeutics · 2024Pooled it
- Pan-cancer single-cell and spatial transcriptomics analyses delineate response-associated heterogeneity and therapeutic targets of tumor-infiltrating B cells following immune checkpoint blockade.Cancer immunology, immunotherapy : CII · 2026Article
- Acquired resistance of cancer therapies: Mechanisms and perspectives.Chinese medical journal · 2026Review
- Integrative Single-Cell and Machine Learning Analysis Identifies an EMT-Associated Prognostic Signature for Papillary Thyroid Cancer.Cancer medicine · 2026Article
- Mechanisms and therapeutic potential of YTHDF readers: Linking epitranscriptomics to cancer.Journal of pharmaceutical analysis · 2026Review
- The shifting paradigm of programmed cell death ligand 1 (PD-L1) in anaplastic thyroid carcinoma: from pathology to clinical practice.Virchows Archiv : an international journal of pathology · 2026Review
- Glutamine-mediated crosstalk between M2 macrophages and tumor cells via the SLC38A5/FOXM1/CNIH4 axis promotes oral squamous cell carcinoma progression.Journal of translational medicine · 2026Article
- Methyltransferase like 3 promotes thyroid folliculogenesisJournal of translational internal medicine · 2026Article
- Reprogramming tumor-associated macrophages in DMG/DIPG: emerging molecular and biophysical strategies.Frontiers in immunology · 2026Review
- Exosome-orchestrated network in gastric cancer: mechanisms, immune regulation, biomarkers and therapeutic vehicles.Frontiers in cell and developmental biology · 2026Review
- Molecular innate immune programs of tumor-associated macrophages in immune checkpoint blockade resistance: a staged framework from suppressive circuitry to translational bottlenecks.Frontiers in immunology · 2026Review
- Adenosine signaling in tumor immune escape: metabolic checkpoints, myeloid suppression, and combination immunotherapy.Frontiers in oncology · 2026Review
- Roles and subtypes of cancer-associated fibroblasts (CAFs) in thyroid cancer.American journal of cancer research · 2026Review
- RNA modifications: roles in immune cell biology and tumor regulation.Cancer cell international · 2025Review
- Extracellular vesicles derived from pro-inflammatory M1 macrophages induce an inflammatory and invasive phenotype in melanoma cells.Cell communication and signaling : CCS · 2025Article
- Spatial Transcriptomics Reveals Transcriptomic and Immune Microenvironment Reprogramming during Thyroid Carcinoma Dedifferentiation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- ZEB1 and ALKBH5 coregulate CRABP2 and FABP5 and jointly determine the sensitivity of anaplastic thyroid cancers to gemcitabine and retinoic acid.NPJ precision oncology · 2025Article
- Exosome-mediated metabolic reprogramming: effects on thyroid cancer progression and tumor microenvironment remodeling.Molecular cancer · 2025Review
- Single-Cell RNA Sequencing Reveals the Heterogeneity in Differentiation Trajectory and Tumor Microenvironment Leading to More Aggressive Phenotypes of Papillary Thyroid Cancer in Children and Young Adult Patients.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The mMolecular biomedicine · 2025Review
5 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
The treatment options for advanced papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) refractory to standard therapies are limited. Although anti-PD-1 therapy has a manageable safety profile and has been effective in a small percentage of patients with advanced PTC and refractory ATC, the majority of the patients either do not respond or develop resistance to anti-PD-1 therapy. N6-methyladenosine (m6A) modification is a critical determinant of the complexity of the tumor microenvironment (TME). However, it is unclear whether and how m6A modification in tumor cells shapes the immune landscape of PTC and ATC. In this study, we performed bulk and single cell RNA sequencing analysis of PTC and ATC tissues, and found that low METTL3 expression not only correlated to poor response to immune checkpoint blockade (ICB) but was also associated with increased TNF family-related ligand-receptor interactions in the immunosuppressive Tregs and exhausted T cells. Furthermore, overexpression of METTL3 in PTC and ATC cells enhanced the efficacy of anti-PD-1 therapy in a peripheral blood mononuclear cell humanized NCG (huPBMC-NCG) mouse model. Mechanistically, M2 macrophage-derived extracellular vesicles (M2 EVs) inhibited METTL3 expression in PTC and ATC cells via miR-21-5p. Downregulation of METTL3 promoted demethylation of CD70 mRNA, which prevented YTHDF2-mediated degradation of the transcripts. The stabilization of CD70 mRNA, and the subsequent upregulation in CD70 protein levels increased the abundance of the immunosuppressive Tregs and terminally exhausted T cells, thereby inducing resistance to anti-PD-1 therapy. Furthermore, blocking CD70 using cusatuzumab, a high-affinity monoclonal antibody, reversed the anti-PD-1 therapy resistance induced by M2 EVs in vivo. Finally, we demonstrated that METTL3 expression negatively correlated with CD70 expression and M2 macrophages and Tregs infiltration in PTC and ATC tissues. Our findings provide new insights into developing novel therapies for advanced PTC and ATC.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.