{
  "abstract": "Isocitrate dehydrogenase (IDH) is the most frequently mutated metabolic enzyme in human cancers. Mutant IDH produces the oncometabolite D-2-hydroxyglutarate (D-2HG), which promotes tumorigenesis in part through epigenetic alterations. Beyond its cell-autonomous effects, tumor-derived D-2HG acts as a potent immunosuppressant that establishes an immune-cold tumor microenvironment. However, the mechanism by which D-2HG is released from tumors remains largely unknown. Here, we identify the SWELL1 (LRRC8A)/LRRC8C-containing volume-regulated anion channel (VRAC) as a principal pathway for D-2HG efflux from IDH-mutant cells. Genetic deletion of SWELL1, the essential VRAC subunit, markedly reduces D-2HG release and reverses associated immunosuppression in an orthotopic mouse model of IDH-mutant glioma. Strikingly, loss of VRAC causes intracellular accumulation of D-2HG, which paradoxically limits tumor cell proliferation by driving epigenetic remodeling and mitochondrial metabolic stress. Pharmacological inhibition of VRAC with dicumarol suppresses IDH-mutant glioma growth, enhances intratumoral T cell activation, synergizes with immune checkpoint blockade, and prolongs survival in tumor-bearing mice. In human IDH-mutant lower-grade gliomas, elevated LRRC8C expression correlates with DNA hypermethylation and an immunosuppressive tumor microenvironment (TME), and predicts poor overall survival. Together, these findings establish VRAC-mediated D-2HG export as a central mechanism regulating both immune evasion and tumor cell fitness, uncovering new therapeutic opportunities across IDH-mutant cancers.",
  "abstract_shown": true,
  "affiliations": [
    "Johns Hopkins University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "H. Y. Cheng"
    },
    {
      "name": "L. Ma"
    },
    {
      "name": "J. Chen"
    },
    {
      "name": "J. Huang"
    },
    {
      "name": "L. Chen"
    },
    {
      "name": "W. Liu"
    },
    {
      "name": "Y. Liu"
    },
    {
      "name": "R. Zhao"
    },
    {
      "name": "Y. Ye"
    },
    {
      "name": "W. Zheng"
    },
    {
      "name": "L. Kratz"
    },
    {
      "name": "M. Castro"
    },
    {
      "name": "S. Sun"
    },
    {
      "name": "J. Zhu"
    },
    {
      "name": "L. Han"
    },
    {
      "affs": [
        0
      ],
      "name": "Z. Qiu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1eja0rqzt2gz2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.18.752798",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1.full",
  "id": "1eja0rqzt2gz2",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7214021436",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1eja0rqzt2gz2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:47Z",
      "native_id": "10.64898/2026.09.18.752798",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas",
  "title_text": "SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:47Z",
  "url": "https://research.draconitic.com/paper/1eja0rqzt2gz2",
  "venue": "bioRxiv",
  "versions": []
}