In the present study, we showed that the double KO of POLQ and FANCD2, two important components of the DNA damage repair/replication stress response genes, leads to (1) an exacerbated level of micronuclei-harboring ESCC cells, (2) overexpression of ISGs including CCL5 in ESCC cell lines and subcutaneous tumors, (3) upregulation of cGAS, and (4) exacerbated phosphorylation of STAT1 at Tyr 701. Here, CCL5 is linked to esophageal squamous cell carcinoma.