Augmenting Tumor Lysis and Immune Response through HIFU-armed Oncolytic Virus Delivery System

Oncolytic viruses (OVs) have hold great promise as a tumor immunotherapy. However, their effectiveness is hindered by the challenge of precise and efficient delivery in vivo and stimulating a robust anti-tumor immune response. In this study, we developed a strategy of high-intensity focused ultrasound (HIFU)-armed oncolytic immunotherapy. It was found that HIFU facilitating efficient delivery of erythrocyte-hijacking OVs to solid tumors and enhancing the penetration of OVs in tumors. Remarkably, HIFU enhanced the oncolytic effect of OVs not only by suppressing the host cell’s ability of virus clearance through downregulating the IFN signaling pathway, but also by enhancing OV replication within tumor cells through upregulating the expression of the oncogene RAS, inducing DNA damage, and promoting OVs-induced autophagy. More importantly, HIFU augmented OVs-mediated anti-tumor immune responses in vivo, leading to remodeling of the tumor microenvironment, resulting in nearly complete tumor regression (97.6 %) within 15 days and 80 % tumor-free status sustained for 120 days. Overall, these findings highlight the potential of HIFU as a novel modality for precise OV delivery, augmented oncolytic effect, and robust immunostimulation in oncolytic immunotherapy of solid tumors.