Journal Club

Antigen- presenting cell activation requires intrinsic and extrinsic STING signaling after the phagocytosis of DNA-damaged cells

Science Immunology 2024

Antigen- presenting cells (APCs) are readily activated after phagocytosing infected or DNA-damaged cells but not

normal apoptotic cells for reasons that are not well understood. Here, we demonstrate that after DNA damage

events, cytosolic dsDNA species trigger intrinsic STING signaling and the production of key immunogenic pro-

teins, including CCL5, which renders such cells capable of APC activation upon phagocytosis. These events involve

the generation of immunogenic STING-inducible endosomal vesicles (SIEVEs) additionally comprising critical

autophagy- associated proteins associated with cytosolic DNA species. After phagocytosis, extrinsic cGAS-STING

signaling is triggered via engulfed, immunogenic transactivating DNA vesicles resulting in APC stimulation. These

results help explain how APCs are predominantly activated by DNA-damaged or infected cells in contrast with

normal apoptotic cells and suggest that reconstitution of STING signaling or key inducible genes in cGAS-STING–

defective malignancies could substantially augment cancer immunotherapies.