Molecular Medicine Israel

STING licensing of type I dendritic cells potentiates antitumor immunity

Editor’s summary

Activation of the DNA sensing cGAS/STING pathway in tumors has opposing host-protective or tumor-promoting responses, depending on the tissue context. STING is broadly expressed by host cells, making its role in tumor control complex. To investigate the role of immune cell subsets in STING-mediated antitumor immunity, Wang et al. generated a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” mode of dual STING signaling. Activation of STING in host conventional type 1 dendritic cells (cDC1s) was crucial for STING-mediated tumor rejection in mice. Furthermore, the presence of STING-activated cDC1s in human tumors correlated with better patient survival. These findings suggest that targeting STING in cDC1s may be an effective strategy to promote antitumor immunity. —Hannah Isles


Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP 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 that conventional type 1 dendritic cells (cDC1s) are essential for STING-mediated rejection of multiple established and metastatic murine tumors. STING status in the host but not in the cancer cells (Tmem173−/−) is important for antitumor efficacy. Specific depletion of cDC1 (Batf3−/−) or STING deficiency in cDC1 (XCR1creSTINGfl/fl) abolished PolySTING efficacy, whereas depletion of other myeloid cells had little effect. Adoptive transfer of wild-type cDC1 in Batf3−/− mice restored antitumor efficacy, whereas transfer of cDC1 with STING or IRF3 deficiency failed to rescue. PolySTING induced a specific chemokine signature in wild-type but not Batf3−/− mice. Multiplexed immunohistochemistry analysis of STING-activating cDC1s in resected tumors correlates with patient survival. Furthermore, STING-cDC1 signature was increased after neoadjuvant pembrolizumab therapy in patients with non–small cell lung cancer. Therefore, we have defined that a subset of myeloid cells is essential for STING-mediated antitumor immunity with associated biomarkers for prognosis.

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