Dimethyl Fumarate Mediates Glutathione Metabolism to Drive Cuproptosis and Activate the Antitumor Function of CD8+ T Cells Against Liver Cancer.

Authors

Jianqiao Kong, Jianjun Tang, Peng Zhang, Yun Zhao, Yang Dai, Zhenghua Ding

Published in

Journal of immunotherapy (Hagerstown, Md. : 1997). Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Dimethyl fumarate (DMF) exerts cytoprotective effects via antioxidant pathway activation. Whether it modulates antitumor immunity through novel cell death forms remains unclear. GSH/GSSG levels were measured in HCC and adjacent tissues using assay kits, with FDX1 and GCLM expression detected by IHC. Cuproptosis-related proteins (NRF2, FDX1, LIAS) and DLAT oligomerization were assessed by western blotting and immunofluorescence in HCC cells. Intracellular GSH, glutamate, Cu2+, and γ-GCS activity were measured biochemically. Cell viability was determined by CCK-8. CD8+ T cells cocultured with HCC cells were analyzed for GZMB, IFN-γ, and TNF-α by flow cytometry; cytotoxicity was evaluated by LDH release. HCC tissues exhibited elevated GSH, downregulated FDX1, and upregulated GCLM compared with adjacent tissues. Elesclomol-Cu2+ (ES-Cu) induced cuproptosis, upregulating NRF2, downregulating FDX1 and LIAS, promoting DLAT oligomerization, and causing GSH depletion and Cu2+ accumulation; GSH-MEE reversed these effects. DMF inhibited GSH metabolism, evidenced by NRF2 downregulation, decreased GSH, increased GSSG, and suppressed γ-GCS activity. Mechanistically, DMF promoted cuproptosis via NRF2 inhibition, which was reversed by NRF2 overexpression. DMF-induced cuproptosis enhanced TNF-α, IFN-γ, and GZMB expression and increased CD8+ T-cell cytotoxicity; the copper chelator tetrathiomolybdate blocked these effects. DMF induces cuproptosis by modulating GSH metabolism, thereby activating CD8+ T-cell-mediated anti-HCC immunity. This offers potential targets for novel combination therapeutic strategies.

PMID:
42836301
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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