Recent progress of PROTACs in cancer immunotherapy.

The recent paradigm shift in cancer therapy-from surgical resection, chemotherapy or radiotherapy toward immunotherapy-indicates that our approach to disease treatment has evolved from exogenous, nonspecific eradication to endogenous, precise modulation of pathogenic factors. As an emerging technology, proteolysis-targeting chimera (PROTAC) has demonstrated considerable potential for treating various protein-driven diseases, and research exploring its application in cancer immunotherapy is rapidly expanding. Compared with the occupancy-driven mode of monoclonal antibodies or small-molecule inhibitors, the most prominent feature of PROTAC lies in its event-driven mode, which efficiently catalyzes the degradation of the vast majority of proteins of interest (POI) that can be specifically bound by ligands. This catalytic degradation property constitutes the core mechanism that has garnered significant interest in PROTAC from the scientific community and facilitated its application in various cancer immunotherapies. Fundamentally, PROTAC eliminates, rather than merely inhibits the POI, thereby completely abolishing its function. This mechanism provides a solid foundation for its application in modulating complex immune networks. To keep pace with the rapid development in this fast-growing and dynamic field, this review briefly summarizes the mechanism of PROTAC and then focuses on elaborating its latest progress in degrading immune checkpoints, modulating functional proteins in immune cells, and reshaping the tumor-suppressive microenvironment. Finally, we elucidate its potential applications in the preparation of therapeutic cancer vaccines and in mitigating chimeric antigen receptor (CAR)-T cell cytotoxicity. We aim to provide scientific evidence and new insights to guide the development of novel PROTAC molecules for application in more effective cancer immunotherapies.