Tumor cell-driven exosomes (TExo) have exhibited several major drawbacks that hinder antitumor therapy. A representative immunosuppressive mechanism is the depletion of CD8+ cytotoxic T cells with the help of exosomal PD-L1. Another common mechanism is to promote tumor metastasis by promoting the seeding and growth of metastatic cancer cells in distant organs. Therefore, the removal of TExo can provide many benefits for the treatment of cancer patients. Here, a bioorthogonal reaction-driven exosome elimination (Biordee) strategy that promoted macrophage-mediated phagocytosis by using IgG Fc to engineer endogenous TExo (TExo-Fc) was developed. The Biordee strategy effectively reduced the levels of TExo in the circulatory system by leveraging the interaction of IgG Fc with FcγRII/III receptors of macrophage, which further broke down the body's immunosuppression and enhanced the immune response after chemotherapy. Moreover, the Biordee strategy inhibited breast cancer liver metastases, which were enhanced by promoting chemotherapy-induced TExo release. This work provided a new attempt to reduce TExo level after chemotherapy to enhance antitumor therapeutic effects.