Summary Colorectal cancer (CRC) is characterized by therapeutic resistance and an immunosuppressive tumor microenvironment (TME). In the present study, five oncolytic herpes simplex virus type 1 (oHSV) variants were constructed based on the herpes simplex virus type 1 (HSV-1) strain 17 via deletion of the IR and ICP47 genes and insertion of the genes encoding mIL-12, mIL-15, and mCCL5. In vitro, these viruses exhibited replication kinetics comparable to those of the wild-type virus, stably expressed the transgenes, and exerted dose- and time-dependent oncolytic effects against colorectal cancer cells. In vivo, the triple-gene-armed oHSV RG2012m remodeled the tumor microenvironment by recruiting and activating immune cells as well as promoting their survival, thereby enhancing antitumor efficacy. Specifically, it elevated the levels of antitumor cytokines and cytotoxic molecules while reducing the abundance of immunosuppressive factors. These oncolytic herpes simplex viruses may function via an "oncolysis-chemotaxis-immune activation" cascade, providing a preclinical rationale for the treatment of colorectal cancer.
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