Bothβ-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 limite...Bothβ-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 andβ-catenin.Inspired by the PRO-teolysis 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 bothβ-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 ofβ-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 byβ-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.展开更多
基金supported by National Natural Science Foundation of China,China(No.82322073,82173846,82304790,82304533)Ori-ental Scholars of Shanghai Universities,China(TP2022081)+13 种基金Jiangxi Province Thousand Talents Program,China(jxsq2023102168)Young Talent Lifting Project of China Association of Chinese Medicine,China[CACM-(2021-QNRC2-A08)]Shanghai Rising-Star Program,China(22QA1409100)2021 Shanghai Science and Technology Innovation Action Plan,China(21S11902800)China Postdoctoral Innovative Talent Support Program,China(BX20220213)Shanghai Sailing Pro-gram,China(22YF1445000,23YF1442600)Three-year Action Plan for Shanghai TCM Development and Inheritance Program,China[ZY(2021-2023)-0401ZY(2021-2023)-0208]Organizational Key Research and Development Program of Shanghai University of Tradi-tional Chinese Medicine,China(2023YZZ02)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine,China(ZYYCXTD-D-202004)CAMS Innovation Fund for Medical Sciences(CIFMS),China(2023-I2M-3-009)Key project at central government level:The ability establishment of sustainable use for valuable Chinese medicine resources,China(2060302)High level Key Discipline of National Administration of Traditional Chinese Med-icine,China(No.zyyzdxk-2023071)Innovation team of high-level local universities in Shanghai:Strategic Innovation Team of TCM Chemical Biology,China.
文摘Bothβ-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 andβ-catenin.Inspired by the PRO-teolysis 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 bothβ-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 ofβ-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 byβ-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.
