Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma
- E. Perpiñán
- N. Sompairac
- D. Marin Correa
- E. Ramon-Gil
- RCH Man
- D. Camell-Raventos
- R. Savoldelli
- M. Fleming
- L. Bellersheim
- CX Santos
- M. Elgosbi
- JJ Lozano
- M. Maddaloni
- C. Schmidl
- E. Kodela
- M. Piqué-Gili
- AH 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
- AM Shah
- GO Fruhwirth
- AT Dinkova-Kostova
- EL Pearce
- J. Leslie
- JM Llovet
- A. Sánchez-Fueyo
- N. Safinia
2026-07-13
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.