Antifibrotic therapy augments the antitumor effects of vesicular stomatitis virus via reprogramming tumor microenvironment.

Solid tumors are characterized by abundant extracellular matrix originating from cancer-associated fibroblasts (CAFs). High collagen content can trigger the collapse of vascular system in the tumor and form physical barrier that eventually impedes the penetration of drug particles and cytotoxic immune cells. Moreover, CAFs are able to promote the enrichment of tumor-associated macrophages (TAMs) and differentiation of myeloid-derived suppressor cells (MDSCs) that work in concert to develop a highly immunosuppressive tumor microenvironment (TME). In this study, we investigated if halofuginone, an anti-fibrotic drug can augment the therapeutic effects of oncolytic vesicular stomatitis virus (VSV). The results revealed that halofuginone significantly disrupts the collagen network in tumors and promotes the distribution of VSV and infiltration of CD8 T cells (P＜0.0001). Combined treatment with VSV and halofuginone also modulates the immunosuppressive TME via deletion of TAMs, MDSCs and regulatory T cells (Tregs). Collectively, the combination therapy remarkably inhibits the tumor growth in multiple murine models and prolongs the survival of mice. The results demonstrate the clinical potential of halofuginone in combination with oncolytic virus.