In the present study, we showed that Rap enhanced MYXV-mediated GBC oncolysis in vitro, but not in vivo. Furthermore, we demonstrated that collagen IV was a critical factor hindering intratumoral MYXV distribution and it limited MYXV-mediated anti-tumor effects in vivo. Finally, HA-induced Akt activation and MMP-9 production significantly improved host survival following MYXV + HA therapy. Here, AKT1 is linked to neoplasm.