ArticleCancer discovery2014
The immune microenvironment confers resistance to MAPK pathway inhibitors through macrophage-derived TNFα.
Article in Cancer discovery, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 150 papers.
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Who cites it
150 citing papers in PubMed, 206 citations in OpenAlex.
- MITF-Driven melanoma plasticity as a core mechanism of therapy resistance: integrating microenvironmental signaling, mechanotransduction, and metabolic reprogramming.Cell cycle (Georgetown, Tex.) · 2026Review
- Regression-Associated Macrophages Recruit Natural Killer Cells That Constrain Targeted Therapy Resistance.Cancer research · 2026Article
- Uncovering the Intricate and Heterogeneous Cellular Microenvironment of Cutaneous Melanoma.Medicina (Kaunas, Lithuania) · 2026Review
- Tissue-specific inflammation induces cell state plasticity with oncogenic addiction in mucosal melanoma.Science advances · 2026Article
- A Case of Immunotherapy Response to BRAFCancer reports (Hoboken, N.J.) · 2026Article
- BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations.Molecular biomedicine · 2026Review
- A bittersweet symphony: soluble mediator networks orchestrate melanoma plasticity and therapeutic adaptation.Frontiers in cell and developmental biology · 2026Review
- BRAF mutation and tumor immune microenvironment in new era.American journal of cancer research · 2026Review
- Integrative bioinformatics screening of a M2 macrophage-associated gene signature for osimertinib resistance.Frontiers in genetics · 2026Article
- Receptor tyrosine kinase inhibitor tivozanib regulates cell state plasticity and restores MITF dependency in BRAF wild-type melanoma.Acta pharmacologica Sinica · 2025Article
- Molecular Basis of BRAF Inhibitor Resistance in Melanoma: A Systematic Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Spatial determinants of tumor cell dedifferentiation and plasticity in primary cutaneous melanoma.bioRxiv : the preprint server for biology · 2025Article
- Targeting the MAPK signaling pathway: implications and prospects of flavonoids in 3P medicine as modulators of cancer cell plasticity and therapeutic resistance in breast cancer patients.The EPMA journal · 2025Article
- Immunosuppressive tumor microenvironment and advance in immunotherapy in melanoma bone metastasis.Frontiers in immunology · 2025Review
- Identification of immunogenic cell death signature genes in hepatocellular carcinoma: from single-cell transcriptomics toFrontiers in immunology · 2025Article
- Integrated transcriptomic analysis reveals a CEBPB-DUSP1 axis driving tumor progression in colorectal cancer.PloS one · 2025Article
- Single-cell and spatial transcriptomics reveal SPP1-CD44 signaling drives primary resistance to immune checkpoint inhibitors in RCC.Journal of translational medicine · 2024Article
- Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance.International journal of molecular sciences · 2024Review
- Crosstalk of pyroptosis and cytokine in the tumor microenvironment: from mechanisms to clinical implication.Molecular cancer · 2024Review
- Mechanisms of resistance to tyrosine kinase inhibitor-targeted therapy and overcoming strategies.MedComm · 2024Review
90 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 1 institution in 1 country.
Funding
Abstract
unlabelledRecently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAF(V600E) melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα signaling with IκB kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma. SIGNIFICANCE: This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNFα, and reveals that in patients on treatment this source becomes reinforced. Inhibiting IκB kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma.
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Registered trials
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 OpenQuestion graph.