STING Activation in Dendritic Cells Enhances Antigen Presentation by Live Tumor Cells

ABSTRACT The stimulator of interferon genes (STING) pathway is a key regulator of antitumor immunity. Activation of STING by the natural agonist 2′3′‐cyclic GMP‐AMP (cGAMP) induces type I interferon and promotes CD8 + T cell responses against tumors. However, how type I interferon modulates tumor cell recognition by T cells remains unclear. Here, using a co‐culture model and virus‐like particles encapsulating cGAMP (cGAMP‐VLP), we show that STING activation in dendritic cells enhances CD8 + T cell recognition of live tumor cells through type I interferon signaling. This effect is independent of enhanced cross‐presentation of soluble or tumor‐associated antigens. Instead, type I interferon produced downstream of STING signaling drives MHC‐I upregulation on tumor cells, which is required for T cell activation. In vivo, host STING activation with cGAMP‐VLP improves the efficacy of immune checkpoint blockade, particularly in tumors lacking cGAS. Together, these findings identify a transcellular mechanism whereby STING activation in dendritic cells increases tumor cell MHC‐I expression to enhance CD8 + T cell‐mediated tumor recognition.