SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas
- 1Johns Hopkins University
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.
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BibTeX
@misc{cheng2026swell1,
title = {{SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas}},
author = {H. Y. Cheng and L. Ma and J. Chen and J. Huang and L. Chen and W. Liu and Y. Liu and R. Zhao and Y. Ye and W. Zheng and L. Kratz and M. Castro and S. Sun and J. Zhu and L. Han and Z. Qiu},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.18.752798},
url = {https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas
AU - H. Y. Cheng
AU - L. Ma
AU - J. Chen
AU - J. Huang
AU - L. Chen
AU - W. Liu
AU - Y. Liu
AU - R. Zhao
AU - Y. Ye
AU - W. Zheng
AU - L. Kratz
AU - M. Castro
AU - S. Sun
AU - J. Zhu
AU - L. Han
AU - Z. Qiu
PY - 2026
DA - 2026/09/18
PB - bioRxiv
DO - 10.64898/2026.09.18.752798
UR - https://www.biorxiv.org/content/10.64898/2026.09.18.752798v1
AB - 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.
ER -