{
  "abstract": "To investigate whether hypoxic conditioning of neuroblastoma (NB) cells induces CD8+ T cell dysfunction/exhaustion-like phenotype via the HIF-1α/PD-L1 axis and whether targeting this axis reverses immune suppression. Human NB cell lines SK-N-SH, SK-N-BE(2), and SK-N-AS were exposed to 1% O₂ hypoxia. HIF-1α and PD-L1 expression were assessed by Western blot, qRT-PCR, and flow cytometry. ChIP-qPCR and dual-luciferase assays were used to verify HIF-1α binding and transcriptional activation of the PD-L1 promoter. SK-N-SH cells pre-conditioned under normoxia or hypoxia were co-cultured with primary human CD8+ T cells. CD8+ T cell dysfunction/exhaustion-like phenotype (PD-1+TIM-3+), apoptosis, IFN-γ, Granzyme B, CD107a, and specific cytotoxicity were evaluated. HIF-1α siRNA, YC-1, and PD-L1 neutralizing antibody were applied. The direct effect of YC-1 on T cells was also assessed. Hypoxia increased HIF-1α and PD-L1 expression in a time-dependent manner and also upregulated PD-L1 in additional NB cell lines. ChIP-qPCR and dual-luciferase assays confirmed direct HIF-1α binding to the HRE (5'-AGGTGC-3') and transcriptional activation. PD-L1 elevation declined after reoxygenation. Hypoxia-preconditioned NB cells increased PD-1+TIM-3+ CD8+ T cells (5.49%-32.24%) and apoptosis (10.61%-26.89%), while reducing IFN-γ+, Granzyme B+, CD107a+ cells and specific cytotoxicity (79.94%-38.40%). HIF-1α knockdown or PD-L1 blockade alleviated these effects. YC-1 at 25 μM did not significantly affect T cell viability or IFN-γ secretion. Hypoxic conditioning of NB cells stabilizes HIF-1α, enhances its binding to the PD-L1 promoter HRE, upregulates PD-L1, and induces CD8+ T cell dysfunction/exhaustion-like phenotype and impaired antitumor function. Targeting HIF-1α or PD-L1 partially restores T cell function in this co-culture model. The hypoxia-driven HIF-1α/PD-L1 axis contributes to immune suppression in NB and may be a potential therapeutic target.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pediatrics, the 960th Hospital of PLA Joint Logistics Support Force, Jinan, Shandong, China.",
    "Department of Oncology, the 960th Hospital of PLA Joint Logistics Support Force, Jinan, Shandong, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Yujin Chao"
    },
    {
      "affs": [
        1
      ],
      "name": "Guili Zheng"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/67nbj3g5cdpan.bib",
  "cited_by": 0,
  "doi": "10.3389/fped.2026.1923893",
  "fulltext_url": "https://europepmc.org/articles/PMC13713678",
  "id": "67nbj3g5cdpan",
  "issns": [
    "2296-2360"
  ],
  "landing_url": "https://europepmc.org/article/MED/42952771",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7221765058",
  "pdf_url": "https://europepmc.org/articles/PMC13713678?pdf=render",
  "pmcid": "PMC13713678",
  "pmid": "42952771",
  "published": "2026-10-14",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/67nbj3g5cdpan.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:41Z",
      "native_id": "MED:42952771",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42952771"
    },
    {
      "first_seen": "2026-10-31T12:24:11Z",
      "native_id": "PMC13713678",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fped.2026.1923893"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Hypoxic conditioning of neuroblastoma cells promotes CD8⁺ T-cell dysfunction through the HIF-1α/PD-L1 axis.",
  "title_text": "Hypoxic conditioning of neuroblastoma cells promotes CD8⁺ T-cell dysfunction through the HIF-1α/PD-L1 axis.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:18Z",
  "url": "https://research.draconitic.com/paper/67nbj3g5cdpan",
  "venue": "Frontiers in pediatrics",
  "versions": []
}