Advances in targeted protein degradation for cancer immunotherapy

Immunotherapy has achieved remarkable clinical success, yet its efficacy remains constrained by immune escape, acquired resistance, and the immunosuppressive tumor microenvironment (TME). A major contributor is the persistent presence of immunosuppressive proteins within tumors and immune cells. Current therapies primarily rely on functional blockade rather than protein elimination, allowing these proteins to continuously sustain immune suppression and drive resistance. Moreover, many immunosuppressive proteins remain "undruggable" due to the lack of suitable binding pockets. Targeted protein degradation (TPD) offers a powerful alternative by selectively eliminating disease-causing proteins. Recent advances have enabled the degradation of intracellular, membrane, and extracellular proteins, significantly expanding the therapeutic landscape. By removing proteins rather than transiently inhibiting them, TPD can achieve more durable antitumor immune responses with reduced resistance. Furthermore, nanosystems enhance TPD by facilitating efficient delivery and promoting protein degradation. This review summarizes recent progress in TPD-based cancer immunotherapy and discusses future directions for next-generation platforms.