Although antibodies are well developed and widely used in cancer therapy and diagnostic fields, some defects remain, such as poor tissue penetration, long in vivo metabolic retention, potential cytotoxicity, patent limitation, and high production cost. These issues have led scientists to explore and develop novel antibody alternatives. Protein scaffolds are small monomeric proteins with stable tertiary structures and mutable residues, which emerged in the 1990s. By combining robust gene engineering and phage display techniques, libraries with sufficient diversity could be established for target binding scaffold selection. Given the properties of small size, high affinity, and excellent specificity and stability, protein scaffolds have been applied in basic research, and preclinical and clinical fields over the past two decades. To date, more than 20 types of protein scaffolds have been developed, with the most frequently used being affibody, adnectin, ANTICALIN®, DARPins, and knottin. In this review, we focus on the protein scaffold applications in cancer therapy and diagnosis in the last 5 years, and discuss the pros and cons, and strategies of optimization and design.
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