Regorafenib presented an antitumor activity in HNSCC mouse model and delayed the tumorigenesis of the 4NQO-indued oral mouse model. By tumor-infiltration lymphocytes isolation and RNA-seq analysis, the immunity-related function was activated by regorafenib. We approved that regorafenib can determine the macrophage polarization toward M1 inflammatory macrophages by suppressing the production of certain cytokines such as plasminogen activator inhibitor-1 (PAI-I) from tumor cells. Also, Regorafenib suppresses secretion of PAI-1 from ex vivo cultures of human HNSCC organoids. Overall design: We performed RNA-seq on tumors from HNSCC mouse model and 4NQO-indued oral mouse model with the treatment of vehicle control, regorafenib, anti-PD1, and regorafenib + anti-PD1