The DIAPH3/RPL6 axis regulates the cGAS-STING pathway in pancreatic cancer.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is essential for regulating immune responses in tumours. The molecular processes regulating its activation in pancreatic cancer remain elusive. We demonstrate that ribosomal protein L6 (RPL6) directly interacts with cGAS, hence initiating cGAS-STING signalling in malignant pancreatic cells. Data mining from open-access sources demonstrated a strong positive connection between RPL6 abundance and immune cell infiltration. The forced expression of RPL6 greatly boosted the production of interferon-β in pancreatic cancer cells. In addition, diaphanous-related formin 3 (DIAPH3) reduced RPL6 protein levels by disrupting its interaction with the deubiquitinase OTUD4. Our results demonstrate that RPL6-mediated stimulation of cGAS-STING signalling profoundly influences immune control in pancreatic cancer, highlighting this pathway as a potential therapeutic target.