The presence of DNA in the cytoplasm of tumor cells induces the dendritic cell to produce type-I IFNs. Classically, the presence of foreign DNA in host cells' cytoplasm during viral infection elicits cGAS-STING mediated type-I IFN signaling and cytokine production. It is likely that cytosolic DNA leads to senescence and immune surveillance in transformed cells during the early stages of carcinogenesis. However, multiple factors, such as loss of cell-cycle checkpoint, mitochondrial damage and chromosomal instability, can lead to persistent accumulation of DNA in the cytoplasm of metastatic tumor cells. That is why aberrant activation of the type I IFN pathway is frequently associated with highly aggressive tumors. Intriguingly, two powerful intracellular deoxyribonucleases, DNase2 and TREX1, can target the cytoplasmic DNA for degradation. Yet the tumor cells consistently accumulate cytoplasmic DNA. This review highlights recent work connecting the lack of DNase2 and TREX1 function to innate immune signaling. It also summarizes the possible mechanisms that limit the activity of DNase2 and TREX1 in tumor cells and contributes to chronic inflammation. © 2022