Molecular erasers: Reprogramming cancer immunity through protein degradation

Antibody-based immunotherapies have transformed cancer treatment, but they face limitations due to pharmacokinetic challenges such as long half-lives, limited tumor penetration, the need for parenteral administration, and immunogenicity. Small molecules present a promising alternative, offering improved oral bioavailability, better tissue permeability, and the ability to target intracellular processes. A substantial advancement in this field is Targeted Protein Degradation (TPD), which utilizes the cell's natural degradation systems to eliminate disease-associated proteins, including those previously deemed "undruggable." This review highlights recent developments in TPD technologies, including proteolysis-targeting chimeras (PROTACs), molecular glues, CLIPTACs, PHOTACs, Folate-PROTACs, AUTACs, ATTECs, LYTACs, and CMA-based degraders. We also explore their applications in cancer immunotherapy, focusing on key regulators such as PD-1/PD-L1, chemokines, TGF-β, IDO1, AhR, and various epigenetic and kinase-associated pathways. Furthermore, we address current engineering challenges, including bioavailability, molecular weight, delivery strategies, and off-target effects and suggest future translational opportunities that integrate nanotechnology, computational modeling, and biomedical engineering to enhance the clinical application of TPD-based immunotherapies.