Recent advances in targeting protein degradation for tumor immunotherapy
Shuai Li, Yushan Jin, Huanhuan Wu, Hong Yuan, Jingyuan Zhao
Abstract
Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the "undruggable" nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies-based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)-within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.