PROTAC delivery in tumor immunotherapy: Where are we and where are we going?

Immunotherapy has emerged as a pioneering therapeutic modality, particularly within the realm of oncology, where Chimeric Antigen Receptor T-cell (CAR-T) therapy has manifested significant efficacy in the treatment of hematological malignancies. Nonetheless, the extension of immunotherapy to solid tumors poses a considerable challenge. This challenge is largely attributed to the intrinsic "cold" characteristics of certain tumors, which are defined by scant T-cell infiltration and a diminished immune response. Additionally, the impediment is exacerbated by the elusive nature of numerous targets within the tumor microenvironment, notably those deemed "undruggable" by small molecule inhibitors. This scenario underscores an acute necessity for the inception of innovative therapeutic strategies aimed at countering the resistance mechanisms underlying immune evasion in cold tumors, thereby amplifying the efficacy of cancer immunotherapy. Among the promising strategies is the deployment of Proteolysis Targeting Chimeras (PROTACs), which facilitate the targeted degradation of proteins. PROTACs present unique advantages and have become indispensable in oncology. However, they concurrently grapple with challenges such as solubility issues, permeability barriers, and the classical Hook effect. Notably, advanced delivery systems have been instrumental in surmounting these obstacles. This review commences with an analysis of the factors contributing to the suboptimal responses to immunotherapy in cold tumors. Subsequently, it delivers a thorough synthesis of immunotherapeutic concepts tailored for these tumors, clarifying the integral role of PROTACs in their management and delineating the trajectory of PROTAC technology from bench- side investigation to clinical utilization, facilitated by drug delivery systems. Ultimately, the review extrapolates the prospective future of this approach, aspiring to present novel insights that could catalyze progress in immunotherapy for the treatment of cold tumors.