biostudies-literatureWan DMajor Science and Technology Project of Hainan ProvinceNational Major Science and Technology Projects of ChinaNational Key Research and Development Program of ChinaCancer Foundation of China200975https://www.ebi.ac.uk/biostudies/studies/S-EPMC11999459biostudies-literatureUnknown33(2)The combination of oncolytic viruses (OVs) with other immunotherapies, such as immunostimulatory therapies, is a current research hotspot; however, optimizing their therapeutic potential remains to be fully explored. Here, we designed a novel oncolytic herpes simplex virus 2 expressing Fms-like tyrosine kinase 3 ligand (OH2-FLT3L), which induces an antitumor cytotoxic T cell immune response by activating dendritic cells (DCs). We found that OH2-FLT3L specifically infects tumor cells, induces immunogenic cell death (ICD), and releases a large number of tumor-specific antigens, which bound to danger signals and facilitated antigenic cross-presentation by DCs, significantly enhancing T cell activation and function. Experimental results showed that OH2-FLT3L significantly increased the proportMolecular therapy. OncologyEngineered oncolytic virus OH2-FLT3L enhances antitumor immunity via dendritic cell activation.PMC119994592023YFC3403300H0923012022ACA001Cheng SXu LZhang WYang ZZhang KZhang XLiu BXie PZhang QWan DfalseEngineered oncolytic virus OH2-FLT3L enhances antitumor immunity via dendritic cell activation.The combination of oncolytic viruses (OVs) with other immunotherapies, such as immunostimulatory therapies, is a current research hotspot; however, optimizing their therapeutic potential remains to be fully explored. Here, we designed a novel oncolytic herpes simplex virus 2 expressing Fms-like tyrosine kinase 3 ligand (OH2-FLT3L), which induces an antitumor cytotoxic T cell immune response by activating dendritic cells (DCs). We found that OH2-FLT3L specifically infects tumor cells, induces immunogenic cell death (ICD), and releases a large number of tumor-specific antigens, which bound to danger signals and facilitated antigenic cross-presentation by DCs, significantly enhancing T cell activation and function. Experimental results showed that OH2-FLT3L significantly increased the proport2025-01-01T00:00:00Z2025 Jun2026-07-15T04:59:05.226Z2026-06-30T03:07:07.538ZS-EPMC119994594023699310.1016/j.omton.2025.200975