Taken together, our results provide several advantages of fascaplysin with newly-identified modes of action for the development of anti-cancer drugs: (1) fascaplysin exerts anti-angiogenic effects via the suppression of VEGFR3, VEGFR2, and HIF-1α; (2) fascaplysin exerts a synergistic effect on TRAIL-based cancer therapies by suppressing survivin expression; and (3) fascaplysin directly suppresses several cancer-related RTKs, such as VEGFR2 and TRKA via DFG-out non-competitive inhibition. Here, FLT4 is linked to cancer.