Small-Molecule PROTACs for Cancer Immunotherapy

Unsatisfactory physicochemical properties of macromolecular drugs seriously hinder their application in tumor immunotherapy. However, these problems can be effectively solved by small-molecule compounds. In the promising field of small-molecule drug development, proteolysis targeting chimera (PROTAC) offers a novel mode of action in the interactions between small molecules and therapeutic targets (mainly proteins). This revolutionary technology has shown considerable impact on several proteins related to tumor survival but is rarely exploited in proteins associated with immuno-oncology up until now. This review attempts to comprehensively summarize the well-studied and less-developed immunological targets available for PROTAC technology, as well as some targets to be explored, aiming to provide more options and opportunities for the development of small-molecule-based tumor immunotherapy. In addition, some novel directions that can magnify and broaden the protein degradation efficiency are mentioned to improve PROTAC design in the future.

Automated summary

Small-molecule compounds can effectively solve the problems of poor physicochemical properties in macromolecular drugs, improving their application in tumor immunotherapy. The proteolysis targeting chimera (PROTAC) technology provides a novel mode of action for small molecules to interact with therapeutic targets, particularly proteins. This review comprehensively summarizes the immunological targets that have been studied and those that are yet to be explored for PROTAC technology, aiming to provide more options and opportunities for small-molecule-based tumor immunotherapy. In addition, it discusses novel directions to enhance and broaden the efficiency of protein degradation in PROTAC design.