Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.

Authors

E Perpiñán, N Sompairac, D Marin Correa, E Ramon-Gil, Rch Man, D Camell-Raventos, R Savoldelli, M Fleming, L Bellersheim, C X Santos, M Elgosbi, J J Lozano, M Maddaloni, C Schmidl, E Kodela, M Piqué-Gili, A H de Sande, R Pinyol, S Higginbotham, Q Peng, E Landman, J Torres-Yaguana, V Sharma, C Zhang, A Kurt, X Liao, T Dowe, M Habarwaa, Z Liu, Y Zen, R Miquel, D Sarker, S Kordasti, T Tree, A M Shah, G O Fruhwirth, A T Dinkova-Kostova, E L Pearce, J Leslie, J M Llovet, A Sánchez-Fueyo, N Safinia

Published in

Nature communications. Jul 13, 2026. Epub Jul 13, 2026.

Abstract

Excessive recruitment and/or activation of regulatory T cells (Treg) into the tumour microenvironment (TME) hamper anti-cancer immunity. Targeting Tregs is therefore a promising strategy to reverse the immunosuppressive features of the TME. Here, we investigate how the development of hepatocellular carcinoma (HCC) impacts the molecular programmes of tissue-resident Tregs. Tregs residing in non-tumoral liver are metabolically inert and prone to apoptosis. Conversely, HCC-infiltrating Tregs activate the nuclear factor erythroid 2-related factor-2 (Nrf2) pathway in response to the lactate-rich TME, which couples redox homeostasis with mitochondrial function and promotes Treg metabolic activity, survival, and suppressive function. Nrf2 loss of function, through either Treg-specific Nfe2l2 ablation or systemic pharmacological inhibition, prevents intra-tumoral Treg accumulation and suppresses cancer growth. Furthermore, patients with advanced HCCs enriched in Tregs with high Nrf2 activation exhibit shorter progression-free survival following atezolizumab/bevacizumab treatment. We propose Nrf2 as a target to disrupt Treg metabolic adaptation within the TME, tipping the balance between effector and regulatory immune cells and reducing cancer progression.

PMID:
42443155
Bibliographic data and abstract were imported from PubMed on 14 Jul 2026.

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