Oncolytic adenovirus synergistically treats liver metastases from colon cancer with PARPi by increasing DNA damage and activating the STING pathway

Background Colorectal cancer (CRC) frequently metastasizes to the liver, leading to a poor prognosis and limited therapeutic options compared to other liver cancers, such as hepatocellular carcinoma (HCC). In this study, we selected the poly (ADP-ribose) polymerase inhibitors (PARPi) and Oncolytic adenoviruses (oAdv) to treat colorectal cancer liver metastases (CRLM). Methods The transcriptional differences between CRLM and HCC were compared using the GSE243245 datasets. The synergistic potential of oAdv and the PARPi was assessed with in vitro and in vivo experiments. The therapeutic efficacy and safety of the combination therapy were evaluated in subcutaneous xenograft and colorectal liver metastasis (CRLM) mouse models. The mechanism of the combination of PARPi and oAdv was further investigated using DNA damage assays and Western blotting (WB). Immune responses to CRLM were assessed using flow cytometry, Western blotting, and ELISpot assays. Results oAdv infection selectively enhanced DNA damage in CRC cells, significantly increasing their sensitivity to AZD2461, while sparing normal hepatocytes. In murine models, the combination therapy demonstrated superior tumor growth inhibition (51.56%) compared to monotherapies. The synergistic effect was particularly pronounced in the CRLM model, correlating with activation of the STING pathway, enhanced immune cell infiltration, and a specific immune response. The therapeutic benefits on the immune response were abrogated by cGAS-Sting pathway inhibition. Conclusion The combination of oAdvand PARPi represents a safe and effective strategy for treating colorectal liver metastases, functioning through tumor-selective enhancement of DNA damage and activation of the cGAS-Sting-mediated immune response.