In this study, we found that the osteosarcoma Rab22a-NeoF1 fusion protein is secreted into exosomes by binding to HSP90 via its KFERQ-like motif, which is taken up by macrophages and cancer cells negative for this fusion gene, and that the exosomal Rab22a-NeoF1 fusion protein can promote its negative recipient cancer cells to metastasize to lungs in mice through the activation of RhoA by its binding partner PYK2 from donor cells. Here, PTK2B is linked to osteosarcoma.