Self-assembled PROTACs enable protein degradation to reprogram the tumor microenvironment for synergistically enhanced colorectal cancer immunotherapy

Both β-catenin and STAT3 drive colorectal cancer (CRC) growth, progression, and immune evasion, and their co-overexpression is strongly associated with a poor prognosis. However, current small molecule inhibitors have limited efficacy due to the reciprocal feedback activation between STAT3 and β-catenin. Inspired by the PROteolysis TArgeting Chimera (PROTAC), a promising pharmacological modality for the selective degradation of proteins, we developed a strategy of nanoengineered peptide PROTACs (NP-PROTACs) to degrade both β-catenin and STAT3 effectively. The NP-PROTACs were engineered by coupling the peptide PROTACs with DSPE-PEG via disulfide bonds and self-assembled into nanoparticles. Notably, the dual degradation of β-catenin and STAT3 mediated by NP-PROTACs led to a synergistic antitumor effect compared to single-target treatment. Moreover, NP-PROTACs treatment enhanced CD103 + dendritic cell infiltration and T-cell cytotoxicity, alleviating the immunosuppressive microenvironment induced by β-catenin/STAT3 in CRC. These results highlight the potential of NP-PROTACs in facilitating the simultaneous degradation of two pathogenic proteins, thereby providing a novel avenue for cancer therapy. • Both β-catenin and STAT3 drives colorectal cancer (CRC) progression. • NP-PROTACs enable dual protein degradation of β-catenin and STAT3 in CRC. • NP-PROTACs reprogram the immunosuppressive microenvironment in CRC. • NP-PROTACs achieve synergistic therapeutic effects in CRC.