This IP enhances anti-tumor immune responses using a chimeric herpes simplex virus (HSV) expressing human interleukin 21 (hIL21). The virus, designated as C021, is engineered to express hIL21, which is inserted into the ICP34.5 locus under the control of a potent MND promoter. Unlike previous generation oHSV, the transcripts produced by C021 are actively translated into cytokines within the tumor environment, leading to higher levels of cytokine production. Preliminary studies in immune-competent mouse tumor models have demonstrated that the expression of IL21 by C021 enhances immune-mediated anti-tumor activity. It increases Natural Killer (NK) and T cell activity in both flank and orthotopic brain tumor models. Additionally, C021 augments the interferon-gamma (IFN-γ) response of NK and CAR-NK cells, with ongoing studies anticipated to show similar effects on CAR-T cells. This versatility positions C021 as a standalone therapeutic or as a complementary treatment alongside adoptive cellular or engineered cellular therapies. The advantages of C021 over existing methods include improved immune activity and anti-tumor efficacy, making it a promising candidate for cancer therapy. Its potential applications extend to CAR therapy markets and beyond, given its compatibility with various engineered cytotoxic therapies.