Innate immune sensing via the cGAS-STING pathway restricts extrachromosomal DNA-driven tumorigenesis.

Extrachromosomal DNAs (ecDNAs) are circular DNA fragments frequently found in human cancers, where they amplify oncogenes, drive tumor heterogeneity, and promote therapy resistance and poor prognosis. Despite their prevalence, how ecDNAs interact with the immune system remains poorly understood. Here, we show that the cytosolic DNA sensor cGAS detects ecDNA fragments in the cytoplasm and activates the innate immune response. cGAS and STING are frequently silenced in ecDNA+ tumors through promoter hypermethylation. Restoring cGAS or STING in human and murine ecDNA+ cancer cells reactivates innate immune signaling and selectively suppresses ecDNA+ tumor growth in an immunocompetent mouse model. Using two ecDNA biogenesis models, we show that the cGAS-STING pathway restricts de novo ecDNA formation. Together, our findings identify innate immune sensing as a natural barrier to ecDNA-driven oncogenesis and establish cGAS-STING reactivation as a therapeutic strategy for ecDNA+ cancers.