STING Licensing of Type I Dendritic Cells Potentiates Antitumor Immunity.

Unlabelled: Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a "shock-and-lock" dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells ( ) is important for antitumor efficacy. Specific depletion of cDC1 ( ) or STING deficiency in cDC1 ( ) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wildtype cDC1 in mice restored antitumor efficacy while transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wildtype but not mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival while also showing increased expressions after neoadjuvant pembrolizumab therapy in non-small cell lung cancer patients. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

One Sentence Summary: A "shock-and-lock" nanoparticle agonist induces direct STING signaling in type 1 conventional dendritic cells to drive antitumor immunity with defined biomarkers.