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. (c) 2023 Elsevier Ltd. All rights reserved.

Automated summary

Cell cycle progression is highly activated in cancer cells, and CDK4/6 inhibition-based cell cycle arrest is a potent cancer treatment strategy. Combining CDK4/6 PROTAC with Chlorin e6-based photodynamic therapy has a synergistic anti-cancer effect, mediated by mitochondria accumulation and activation, resulting in increased production of reactive oxygen species and apoptosis.