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. 2020 Apr 28;11:615. doi: 10.3389/fimmu.2020.00615

FIGURE 5.

FIGURE 5

Cell interactions in TME engaging the cGAS-STING pathway. Double-stranded breaks (DSBs) can lead to cytosolic self-DNA that engages the cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and produces type-I interferon (IFN). STING promotes the senescence of cancer cells. Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) can transfer to proximal host non-cancer cells through gap-junction channels and promote the formation of an inflammatory tumor microenvironment (TME). Dendritic cells (DCs) are the main source of type-I IFN and tumor necrosis factor α (TNFα), and promote an inflammatory TME. Infiltrating DCs take up tumor-derived DNA or cGAMP from dying cell fragments or exosomes. DCs cross-prime and activate anti-tumor cluster of differentiation 8 (CD8)+ T cells and constrict cancer growth effectively. Co-stimulation of type-I IFN and TNFα signaling simultaneously leads to remarkable necroptosis of tumor cells. cGAS can relocate to the nucleus and obstruct polymerase 1 (PARP1), which suppresses DNA repair. Chronic levels of IFNα and TNFα in TME could support tumor development and cause type-2 macrophages and regulatory T cells to be recruited (Red arrows represent mechanisms promoting tumors; black arrows represent mechanisms limiting tumors).