Self-assembled PROTACs enable protein degradation to reprogram the tumor microenvironment for synergistically enhanced colorectal cancer immunotherapy
Xinchen Lu, Jinmei Jin, Ye Wu, Jiayi Lin, Xiaokun Zhang, Shengxin Lu, Jiyuan Zhang, Chunling Zhang, Maomao Ren, Hongzhuan Chen, Weidong Zhang, Xin Luan
Abstract
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.