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Abstract
The stimulator of interferon genes (STING) is a key mediator of anti-tumor immunity, activated downstream of cytoplasmic DNA recognition by cyclic GMP-AMP synthase (cGAS). In cells using the alternative lengthening of telomeres (ALT) pathway, extrachromosomal telomeric repeats (ECTRs) are characteristic features and potent activators of the cGAS-STING pathway. While ALT+ cells were thought to evade this pathway through epigenetic silencing, our findings uncover a more nuanced adaptive mechanism. In most ALT+ cells, ongoing ECTR production supports 2’3’-cGAMP synthesis, directing STING to the Golgi for immune signaling before lysosomal degradation. This process relies on interferon regulatory factor 3 (IRF3), with minimal involvement of TANK-binding kinase 1 (TBK1). Additionally, by promoting autophagy, STING facilitates immunogenic ECTR clearance from the cytosol, preventing prolonged inflammatory signaling. These findings refine our understanding of immune sensing in ALT+ cancers, revealing how ALT+ cells adapt to continuous ECTR production and suggesting a potential therapeutic target to modulate this pathway and compromise the fitness of ALT+ cancers.
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Geelen, D., Beacom, A., Vaurs, M., Mahieu, M., Boutoual, R., Derumier, A., Hoerr, R., Loriot, A., Nassour, J., & Decottignies, A. (2025). Constitutive cGAS-STING activation in ALT+ cells. Telomeres & Telomerase, Cold Spring Harbor USA, Cold Spring Harbor, USA. https://hdl.handle.net/2078.5/247676