CDK4/6 nano-PROTAC enhances mitochondria-dependent photodynamic therapy and anti-tumor immunity

Cell cycle progression in cancer cells is highly activated, making CDK4/6 inhibition-based cell cycle arrest a potent cancer treatment strategy. To enhance therapeutic efficacy, it is crucial to explore CDK4/6 inhibition-based combination strategies. In this study, we found that combing CDK4/6 PROTAC with Chlorin e6-based photodynamic therapy produced a synergistic anti-cancer effect. This combination effect was mediated by mitochondria accumulation and activation, leading to increased production of reactive oxygen species and apoptosis. To promote clinical translation, we developed a self-assembled, carrier-free nanoparticle system to co-deliver these two molecules. The dual-drug nanoparticles not only induced higher apoptosis but also cooperatively induced immunogenic cell death and chemotaxis of immune cells, remodulating immunosuppressive tumor microenvironment to enhance anti-tumor immunity. This study provides a promising strategy to combine G1 cell cycle blockage and photodynamic therapy and advances the broad applications of PROTAC in clinical cancer treatment.