Systemic Propagation of STING Signalling via Generation of Large Extracellular Vesicles

Large extracellular vesicles (EVs) derived from tumour cells play important roles in tumour formation and progression. However, it remains unclear why malignant cells produce these EVs and how they act in vivo. We employ a well-characterized Drosophila tumour model and demonstrate that large EV biogenesis from malignant cells is an evolutionarily conserved process. Our study uncovers an essential role for the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which mediates the innate immune response to cytosolic DNA, in driving large EV biogenesis and inducing a systemic immune response to tumours. STING engages a signalling axis comprising JNK and FAK-independent of TANK-binding kinase 1 (TBK1) and inhibitor of nuclear factor κB kinase (IKKβ)-to drive large EV biogenesis in both Drosophila and human malignant cells. Transplantation of large EVs from Drosophila tumours to wild type larvae is sufficient to recapitulate the systemic immune response to tumours by activating STING signalling in macrophage-like cells. Thus, our study establishes a novel animal model for studying large EVs derived from malignant cells and provides insights into how STING signalling propagates from tumour cells to the immune system via large EV biogenesis, inducing a systemic immune response to tumours.