Self-Assembled Molecular Glue Prodrug System for Enhanced Synergistic Tumor Therapy by Combining CDK12 Protein Degradation and Immunotherapy.

Molecular glue degraders have recently emerged as a promising strategy for targeting proteins previously considered undruggable. Among these, CR8 has demonstrated potent anticancer efficacy by effectively degrading cyclin-dependent kinase 12 and cyclin K. However, its clinical application is restricted by nonspecific toxicity to normal cells and tissues. To address this limitation, we developed a prodrug of CR8, termed pCR8, which selectively releases CR8 at tumor sites through boronate oxidation mediated by elevated HO levels in the tumor microenvironment. Moreover, the amphiphilic prodrug can self-assemble to form nanoparticles. experiments showed that pCR8 exhibits lower cytotoxicity and responds effectively to HO, resulting in the release of CR8, which inhibits 4T1 cells and effectively degrades cell cycle-related proteins. Additionally, the therapeutic efficacy of pCR8 was corroborated in 4T1 tumor-bearing mice through tail vein injection, revealing its tumor-suppressive activity associated with CD8 T cell activation and a synergistic effect when combined with immune checkpoint inhibitors, while also showing improved safety compared with CR8. Our findings suggest that pCR8 not only offers a promising strategy for reducing the side effects of CR8 but also introduces an effective combination therapy approach for the treatment of triple-negative breast cancer.