Cancer's immune escape route mapped—new drug target could unlock stuck immunotherapies
Researchers have identified how tumors reprogram immune cells to suppress anti-cancer defenses, pinpointing a molecular switch called Nrf2 that could be blocked to restore therapy effectiveness. The finding offers a concrete path to improve outcomes for liver cancer patients currently resistant to leading immunotherapies, potentially creating a new class of combination treatments.
Originaltitel: Nrf2-mediated metabolic reprogramming drives regulatory T cell accumulation in hepatocellular carcinoma.
Nrf2-aktivering driver regulatoriska T-celler (Treg) in i tumörmiljön vid levercancer och minskar immunförsvaret mot cancer. Forskargruppen vid King's College London identifierade att Tregs i tumören aktiverar Nrf2-signaleringen som svar på laktatrik miljö, vilket ökar cellernas metabola aktivitet och överlevnad. Genom att blockera Nrf2 — antingen genom genetisk borttagning eller farmakologisk hämmning — minskade Treg-ackumulering och tumörväxt. Patienter med avancerad levercanal som hade högt Nrf2-aktiverade Tregs visade kortare överlevnadstid efter behandling med atezolizumab och bevacizumab. Resultaten öppnar för nya immunterapi-strategier: Nrf2-hämmning kan skifta balansen från immunsuppression till effektiv antitumöral immunitet. För levercanvårdare och immunterapibolag blir detta relevant för utveckling av kombinationsbehandlingar och patientstratifiering med Treg-biomarkörer.
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.