*3.3. Tumor ECM and Vasculature Degradation*

Tumor ECM is a barrier to access tumor cells. Co-administration of ECM-degrading enzymes such as relaxin [234], matrix metalloproteinase (MMP)-1, -8, -9 [131,226], chondroitinase [235], and hyaluronidase [226] with OVT, or induction of their genes expression in GLV-1h255 (VACV) and VCN-01 (OAdV) can increase OV spread into the TME and improved OVT efficiency in cancers such as retinoblastoma and pancreatic carcinoma [236,237]. Cellular tight junctions are also accounted as barriers for OV distribution. GMOVs can trigger the production of proteins such as penton-dodecahedra and junction opener-1, which open the cellular junction through binding to desmoglein-2 [226]. However, there are concerns about increasing the likelihood of metastasis in this method that needs further investigation.

On the other hand, the insertion of endostatin and thrombospondin-1 genes in HSV-Endo and T-TSP-1 (both are HSV) destroys tumor vasculature. It suppresses angiogenesis in lung and gastric cancer by inhibiting migration and enhancing apoptosis in vECs [238,239]. Also, the expression of anti-VEGF sc-Ab by VACV increases antiangiogenic and antitumor properties [240].
