Advances in novel modification strategies for enhancing the tumor tissue specificity of PROTACs.

Proteolysis-Targeting Chimeras (PROTACs), a pioneering Targeted Protein Degradation (TPD) technology, have emerged as a powerful therapeutic modality for cancer by mediating the degradation of proteins via the ubiquitin-proteasome system. Despite their promise, the clinical translation of PROTACs is frequently hampered by significant challenges, including suboptimal pharmacokinetic properties, poor stability, and most critically, a lack of tumor specificity, which can lead to on-target, off-tumor toxicities and a narrow therapeutic window. To address these limitations, a variety of innovative strategies have been developed to enhance the tumor-specific accumulation of PROTACs. This review provides a comprehensive overview of the recent advances in this field. We systematically discuss three major approaches: intrinsic structural modifications of the PROTAC scaffold to confer tissue selectivity; the design of activatable prodrugs that respond to the unique tumor microenvironment; and the development of intelligent nano-delivery systems for targeted release. Collectively, these next-generation modification strategies aim to maximize the therapeutic index of PROTACs by improving their efficacy and safety profiles. This review highlights the technological pathways poised to accelerate the clinical development of tissue-specific protein degraders for oncology.