Advances of research of Fc-fusion protein that activate NK cells for tumor immunotherapy

•We analyzed and summarized the Fc-fusion proteins currently on the market and under development, and drew models of their protein structures..•Different from the immune pathway played by monoclonal antibodies, we summarized the anti-tumor effects of Fc-fusion proteins in inducing NK cells.•We analyzed and summarized three ways that Fc-fusion proteins can induce the anti-tumor effects of NK cells, namely targeting tumor cells, targeting NK cell surface receptors or their ligands, and the serection of NK cell-related cytokines.•In this review we provided an in-depth review of glycosylation modifications in Fc-fusion proteins and the effect of CD16 polymorphism in Fc-protein affinity. The rapid development of bioengineering technology has introduced Fc-fusion proteins, representing a novel kind of recombinant protein, as promising biopharmaceutical products in tumor therapy. Numerous related anti-tumor Fc-fusion proteins have been investigated and are in different stages of development. Fc-fusion proteins are constructed by fusing the Fc-region of the antibody with functional proteins or peptides. They retain the bioactivity of the latter and partial properties of the former. This structural and functional advantage makes Fc-fusion proteins an effective tool in tumor immunotherapy, especially for the recruitment and activation of natural killer (NK) cells, which play a critical role in tumor immunotherapy. Even though tumor cells have developed mechanisms to circumvent the cytotoxic effect of NK cells or induce defective NK cells, Fc-fusion proteins have been proven to effectively activate NK cells to kill tumor cells in different ways, such as antibody-dependent cell-mediated cytotoxicity (ADCC), activate NK cells in different ways in order to promote killing of tumor cells. In this review, we focus on NK cell-based immunity for cancers and current research progress of the Fc-fusion proteins for anti-tumor therapy by activating NK cells.