Several TME’s components promote an immune suppressive environment. Regorafenib modulates immuno-suppressive TME by blocking VEGFRs, TIE2, and CSF-1R, enhancing anti-tumor immunity. Abbreviations: CTL, cytotoxic T lymphocyte; DC, dendric cell; EC, endothelial cell; TAM, tumor-associated macrophage; TEM, TIE2-expressing monocyte/macrophage; TME, tumor microenvironment; Treg, regulatory T cell.