Cytosolic DNA structures produced by mismatch-repair deficiency coordinate anti-tumor immunity in colorectal cancer

Patients with the microsatellite instable (MSI) subtype of colorectal cancer (CRC) have better prognosis and immunotherapy response than patients with the chromosomally instable (CIN) subtype due to improved cytotoxic T cell responses. This is in part due to high production of the chemokines CXCL10 and CCL5 from constitutive activation of the cytosolic DNA (cyDNA) sensor cGAS/STING by specific features of MSI cyDNA that lead to more effective cGAS/STING pathway activation. Here, we investigate MSI and CIN cyDNA structure and show that MSI cyDNA is enriched in G-quadruplexes which improve cGAS/STING and CD8+ T cell activation. We also show that micronuclei are less effective at inducing anti-tumor immunity and instead increase Treg activation and IL10 production. Overall, these data highlight the role of specific cyDNA structures in anti-tumor immunity and provide knowledge for improved design of therapeutic DNA-based cGAS/STING agonists to improve the prognosis of poorly immunogenic tumors like CIN CRCs.