Inactivation of the DNA-sensing pathway facilitates oncolytic herpes simplex virus inhibition of pancreatic ductal adenocarcinoma growth.

Oncolytic viruses are a new class of therapeutic agents for the treatment of cancer that have shown promising results in clinical trials. Oncolytic virus-mediated tumor rejection is highly dependent on viral replication in tumor cells to induce cell death. However, the antiviral immune response of tumor cells limits the replication capacity of oncolytic viruses. We hypothesized that inhibition of the antiviral immune response in infected cells would enhance the antitumor effect. Here, we confirmed that ablation of the key adaptor protein of cellular immunity, STING, significantly suppressed the antiviral immune response and promoted oncolytic herpes simplex virus-1 (oHSV1) proliferation in tumor cells. In a murine pancreatic ductal adenocarcinoma (PDAC) model, oHSV1 enhanced tumor suppression and prolonged the survival of mice in the absence of STING. On this basis, we further found that the TBK1 inhibitor can also significantly enhance the tumor-control ability of oHSV1. Our studies provide a novel strategy for oncolytic virus therapy by inhibiting the intrinsic antiviral response in solid tumors to improve antitumor efficacy.