Figure 3.

DNA damage-induced cGAS-STING activation augments type I IFN signaling-mediated anti-tumor immune responses post chemo-, radio- and immune-therapies

Genome aberration triggers cytosolic DNA accumulation such as micronucleus formation. cGAS binds to DNA in micronuclei and synthesizes cGAMP for subsequent activation of ER-resident STING. STING-TBK1-IRF3/NF-κB signaling is activated for IFN-I transcription. Type I IFN signaling and DNA-containing exosomes activate DCs via facilitating tumor antigen/neoantigen presentation on their MHC. MHC-antigen peptide complexes bind to T cell receptor (TCR) and activate CD8⁺ T cells, but this process may be restricted by the B7:CTLA-4 inhibitory signals. Activated T cells infiltrate tumors and release IFN-γ to mediate the cytotoxic effects against tumor cells, where interaction between PD-1 and PD-L1 antagonizes their anti-tumor activities of the immune effectors. Blockade of PD-1 and CTLA-4 promote the CD8+ T cell anti-tumor responses.