ArticleMolecular cancer2025
IL-4 mediated TAP2 downregulation is a dominant and reversible mechanism of immune evasion and immunotherapy resistance in non-small cell lung cancer.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed.
- GSDME upregulation predicts poor prognosis in gastric cancer.Molecular biology reports · 2026Article
- Integrated multi-omics analysis of post-translational modifications in head and neck squamous cell carcinoma: elucidating x-ray and carbon ion irradiation effects.Precision radiation oncology · 2026Article
- Article
- TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in colorectal cancer.Molecular therapy. Oncology · 2026Article
- LARS2 reprograms mitochondrial metabolism and epigenetically upregulates MHC-I to boost antitumor immunity in nasopharyngeal carcinoma.Journal for immunotherapy of cancer · 2026Article
- The proteomics and phosphoproteomics landscape of melanoma under T cell attack.Cell reports. Medicine · 2026Article
- NSCLC brain metastases exhibit reduced HLA-I antigen presentation machinery and immune evasion independent of IFNγ signaling defects.Molecular cancer · 2026Article
- Chromatin Accessibility in Cancer: Biological Functions, Mechanisms, Therapeutic Potential, and Future Directions.MedComm · 2026Review
- Mechanism of IL-4 mediated RPL19 promoting malignant progression in HER2 positive breast cancer.Breast cancer research : BCR · 2026Article
- The central role of radiotherapy in remodeling the tumor immune microenvironment: mechanisms and therapeutic implications.Frontiers in cell and developmental biology · 2026Review
- Primary and acquired resistance to immunotherapy in NSCLC.Frontiers in immunology · 2026Review
- Adenosine signaling in tumor immune escape: metabolic checkpoints, myeloid suppression, and combination immunotherapy.Frontiers in oncology · 2026Review
- Intravenous iRGD-Guided, RBC-Membrane Camouflaged Lactococcus Lactis Remodels Cold NSCLC and Enhances PD-1 Blockade.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Soil and Seed: Tumor Microenvironment Nurtures Immunotherapy Resistance and Renewal.International journal of molecular sciences · 2025Review
- The role of neoantigens and tumor mutational burden in cancer immunotherapy: advances, mechanisms, and perspectives.Journal of hematology & oncology · 2025Review
- MED12-STAT1-TAP2 axis regulates CD8 + T cell cytotoxicity and mediates immunotherapy outcome in non-small cell lung cancer.Functional & integrative genomics · 2025Article
- Pharmacological strategies to overcome immune checkpoint inhibitor resistance in non-small cell lung cancer.Frontiers in oncology · 2025Review
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10 authors.
Funding
Abstract
backgroundResistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein β-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly understood.
methodsUsing multiplexed immunofluorescence, we spatially mapped CD8
resultsWe identified cancer cell selective TAP2 protein downregulation in 42.4% of treatment naïve NSCLCs associated with reduced sensitivity to immune checkpoint blockers. TAP1 downregulation occurred in 24.4% of lung tumors without survival impact. Silencing of TAP2 in lung cancer cells altered key intracellular immunomodulatory pathways, limited sensitivity to proinflammatory cytokines, reduced the levels of surface peptide-HLA complexes and protected malignant cells from tumor antigen-specific T-cell killing via SOCS1 upregulation. TAP2 loss in human NSCLCs was associated with reduced TAP2 promoter chromatin accessibility and elevated IL-4 IL-4 expression. Treatment with IL-4 reduced TAP2 levels and the chromatin accessibility of the TAP2 gene promoter in NSCLC cells and reproduced all the functional consequences of TAP2 loss. In intact human NSCLC, IL-4 IL-4 transcripts were detected in intratumoral myeloid cells and IL-4Rα blockade increased human NSCLC cell killing by autologous TILs. Epigenetic modulators and other drugs with known anti-cancer activity increased TAP2 expression and its function in lung cancer cells.
conclusionsOur study reveals previously unrecognized functions of TAP2 beyond antigen presentation and establishes a reversible multi-cellular axis mediating adaptive immune evasion and immunotherapy resistance with clinical potential.
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