ArticleMolecular therapy : the journal of the American Society of Gene Therapy2021
Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers, 2 of them syntheses that pooled it.
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Who cites it
86 citing papers in PubMed, 2 syntheses or guidelines pooled it, 113 citations in OpenAlex.
- Differentiation state affects PD-L1 expression in cutaneous melanoma: a systematic review.Cellular & molecular biology letters · 2026Pooled it
- The role of glutamate receptors in the regulation of the tumor microenvironment.Frontiers in immunology · 2023Pooled it
- Recent advancements in NRF2-regulated ferroptosis modulation for targeted cancer therapy.Molecular biology reports · 2026Review
- Targeting the nervous system: Mechanistic insights into neuro-tumor communication and therapeutic opportunities.Acta pharmaceutica Sinica. B · 2026Review
- RanBP2 promotes ferroptosis resistance and compromises therapeutic response by stabilizing SLC7A1 through LRSAM1 SUMOylation and ubiquitination in lung adenocarcinoma.Cell death and differentiation · 2026Article
- The increased co-expression of SLC7A11 and PD-L1 was associated with poor prognosis in extranodal natural killer T-cell lymphoma patients.Cancer immunology, immunotherapy : CII · 2026Article
- Article
- Solute Carrier transporters in tumor metabolism and immune modulation: implications for therapy.Journal of translational medicine · 2026Review
- Tumor-Associated Macrophages as Therapeutic Targets: Deciphering Interaction Networks and Advancing Clinical Translation.MedComm · 2026Review
- TME remodeling and clinical challenges of immune checkpoint blockade in nasopharyngeal carcinoma.Frontiers in oncology · 2026Review
- Epigenetics and One-Carbon Metabolism in Cancer: Mechanisms and Therapeutic Implications.Advances in experimental medicine and biology · 2026Review
- Article
- Mitochondria at the intersections of RNA modifications and metabolism reprogramming implications in cell death, tumor microenvironment, and immunotherapy.Journal of hematology & oncology · 2025Review
- Identification Of Protein Cargo in Extracellular Vesicles from Macrophages in Progressing and Regressing Tumors.bioRxiv : the preprint server for biology · 2025Article
- JMJD3 upregulates ALOX5 to drive malignancy and concomitant ferroptosis sensitivity in gastric cancer.Cell death & disease · 2025Article
- The neuro-immune axis in cancer: from mechanisms to therapeutic opportunities.Journal of hematology & oncology · 2025Review
- Targeting Cystine Metabolism in the Lung Cancer Environment Enhances the Efficacy of Immune Checkpoint Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Role of Solute Carriers in the Metabolic Reprogramming of Skin Diseases.Clinical reviews in allergy & immunology · 2025Review
- B10 cell-induced PD-L1/PD-1-linked macrophage polarization in periodontitis.Journal of translational internal medicine · 2025Article
- Targeting Exosomal PD-L1 as a New Frontier in Cancer Immunotherapy.Current issues in molecular biology · 2025Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Tumor cells increase glutamate release through the cystine/glutamate transporter cystine-glutamate exchange (xCT) to balance oxidative homeostasis in tumor cells and promote tumor progression. Although clinical studies have shown the potential of targeting programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling in melanoma, response rates are low. However, it remains unclear how glutamate metabolism affects anti-PD-1/PD-L1 treatment efficacy in melanoma. Here, we demonstrated that although inhibition of xCT either by pharmacological inhibitor (sulfasalazine [SAS]), approved by US Food and Drug Administration (FDA) for inflammatory diseases, or genetic knockdown induced reactive oxygen species (ROS)-related death in melanoma cells, inhibition of xCT significantly reduced the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade through upregulating PD-L1 expression via the transcription factors IRF4/EGR1, as a consequence, exosomes carrying relatively large amounts of PD-L1 secreted from melanoma cells resulted in M2 macrophage polarization and reduced the efficacy of anti-PD-1/PD-L1 therapy in melanoma. Taken together, our results reveal that inhibition of xCT by SAS is a promising therapeutic strategy for melanoma; on the other hand, SAS treatment blunted the efficacy of anti-PD-1/PD-L1 via exosomal PD-L1-induced macrophage M2 polarization and eventually induced anti-PD-1/PD-L1 therapy resistance.
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