Abstract 4035: SWELL1 controls epigenetic methylation, mitochondrial metabolism, and anti-tumor immunity in IDH-mutant gliomas

Abstract Diffuse gliomas account for the majority of adult brain malignancies with limited therapeutic options. Among them, isocitrate dehydrogenase (IDH)-mutant (mIDH) gliomas occur in the majority of diffuse low-grade gliomas with signatures of epigenetic hypermethylation, disrupted mitochondrial metabolism, and an immunologically “cold” microenvironment. Thus, identifying novel mediator that links these processes is critical for developing new treatments. Here, we identified SWELL1 (also known as LRRC8A) as a critical mediator for the mIDH glioma progression. SWELL1, the essential component of the volume-regulated anion channel (VRAC), has been linked to glucose metabolism, glutamate-mediated neuron toxicity, and ATP-induced microglial activation. In our study, SWELL1 knockout (SKO) in primary mouse mIDH gliomasphere cells resulted in increased epigenetic methylation, together with loss of cellular stemness transcriptional programs. Moreover, metabolomic and Seahorse analyses revealed loss of TCA cycle metabolites and decreased mitochondrial respiration in SKO gliomasphere cells, leading to loss of cell growth activities. These findings were further validated using patient-derived TS603 gliomasphere cells and the analysis of a recently published single-cell RNA-sequencing (scRNA-seq) dataset, in which tumors with low SWELL1 mRNA expression exhibited loss of proliferation and increased inflammation signatures. We further performed orthotopic xenograft model using mouse gliomasphere cells and found that mIDH SKO tumors progress slower with prolonged mouse survival. Within the tumor microenvironment, SKO tumors exhibited a profound immune-reactive phenotypes, with increased microglial and tumor-associated macrophage antigen presenting activation, as well as T cell cytotoxic activation. Importantly, orthotopic tumoral VRAC inhibition with an FDA-approved drug dicumarol phenocopied the genetic knockout, extended survival, and synergized with anti-PD-1 checkpoint blockade, significantly boosting anti-tumor efficacy. Our study identifies SWELL1 as a novel, targetable mediator that couples mitochondrial metabolism and epigenetics to oncogenic progression and immune exclusion in mIDH gliomas, providing a strong preclinical rationale for targeting VRAC as potential IDH-mutant glioma therapeutics. Citation Format: Henry Yi Cheng, Jianan Chen, Jiale Huang, Wenrui Liu, Zhaozhu Qiu. SWELL1 controls epigenetic methylation, mitochondrial metabolism, and anti-tumor immunity in IDH-mutant gliomas abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4035.