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It is widely accepted that siRNA transfection can promote some off-target effects in the genome; however, little is known about how the cells can respond to the presence of non-viral dsRNA. In the present study, non-targeting control siRNA (NTC-siRNA) was used to evaluate its effects on the activity of pathogen and host-derived nucleic acid-associated signaling pathways such as cGAS-STING, RIG-I, MDA5 and NF-κB in A431 skin cancer cells and BJ fibroblasts. NTC-siRNA treatment promoted cytotoxicity in cancer cells. Furthermore, NTC-siRNA-treated doxorubicin-induced senescent cancer cells were more prone to apoptotic cell death compared to untreated doxorubicin-induced senescent cancer cells. NTC-siRNA stimulated the levels of NF-κB, APOBECs, ALY, LRP8 and phosphorylated STING that suggested the involvement of selected components of nucleic acid sensing pathways in NTC-siRNA-mediated cell death response in skin cancer cells. NTC-siRNA-mediated apoptosis in cancer cells was not associated with IFN-β-based pro-inflammatory response and TRDMT1-based adaptive response. In contrast, in NTC-siRNA-treated fibroblasts, an increase in the levels of RIG-I and IFN-β was not accompanied by affected cell viability. We propose that the use of NTC-siRNA in genetic engineering may provoke a number of unexpected effects that should be carefully monitored. In our experimental settings, NTC-siRNA promoted the elimination of doxorubicin-induced senescent cancer cells that may have implications in skin cancer therapies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)