Self-assembled PROTACs enable protein degradation to reprogram the tumor microenvironment for synergistically...

Area of Science:

• Biomedical Engineering
• Oncology
• Molecular Biology

Background:

• β-catenin and STAT3 are key drivers of colorectal cancer (CRC) growth, progression, and immune evasion.
• Co-overexpression of β-catenin and STAT3 correlates with poor prognosis in CRC patients.
• Existing small molecule inhibitors show limited efficacy due to feedback activation between these two proteins.

Purpose of the Study:

• To develop a novel therapeutic strategy using nanoengineered peptide PROTACs (NP-PROTACs) for the simultaneous degradation of β-catenin and STAT3.
• To investigate the efficacy of NP-PROTACs in degrading dual targets and their synergistic antitumor effects in CRC.
• To evaluate the impact of NP-PROTACs on the tumor immune microenvironment.

Main Methods:

• Engineered peptide PROTACs coupled with DSPE-PEG via disulfide bonds to form self-assembled nanoparticles (NP-PROTACs).
• Utilized PROteolysis TArgeting Chimera (PROTAC) technology for selective protein degradation.
• Assessed the dual degradation of β-catenin and STAT3, antitumor efficacy, and immune cell infiltration in CRC models.

Main Results:

• NP-PROTACs effectively achieved simultaneous degradation of both β-catenin and STAT3.
• Dual degradation resulted in a synergistic antitumor effect, superior to single-target inhibition.
• NP-PROTACs treatment enhanced CD103+ dendritic cell infiltration and T-cell cytotoxicity, reducing tumor immunosuppression.

Conclusions:

• NP-PROTACs represent a promising approach for simultaneously degrading pathogenic proteins like β-catenin and STAT3.
• This strategy offers a novel therapeutic avenue for colorectal cancer by overcoming resistance mechanisms and modulating the immune microenvironment.
• The findings support the potential of NP-PROTACs in advancing cancer therapy through targeted protein degradation.