SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas

Cheng, H. Y.; Ma, L.; Chen, J.; Huang, J.; Chen, L.; Liu, W.; Liu, Y.; Zhao, R.; Ye, Y.; Zheng, W.; Kratz, L.; Castro, M.; Sun, S.; Zhu, J.; Han, L.; Qiu, Z.

doi:10.64898/2026.09.18.752798

bioRxiv · 10.64898/2026.09.18.752798

SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas

Cheng, H. Y.·Ma, L.·Chen, J.·Huang, J.·Chen, L.·Liu, W.·Liu, Y.·Zhao, R.·Ye, Y.·Zheng, W.·Kratz, L.·Castro, M.·Sun, S.·Zhu, J.·Han, L.·Qiu, Z.

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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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Cheng, H. Y., Ma, L., Chen, J., Huang, J., Chen, L., Liu, W., Liu, Y., Zhao, R., Ye, Y., Zheng, W., Kratz, L., Castro, M., Sun, S., Zhu, J., Han, L., Qiu, Z.. 2026-09-22. SWELL1 channel-mediated D-2HG export promotes immune evasion and metabolic fitness in IDH-mutant gliomas. https://doi.org/10.64898/2026.09.18.752798

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