摘要
Malignant melanoma cell-intrinsic PD-1:PD-L1 interaction thrusts tumorigenesis,angiogenesis,and radioresistance via mTOR hyperactivation to aggravate circumjacent aggression.Interdicting melanoma intrinsic growth signals,including the blockade of PD-L1 and mTOR signaling concurrently,cooperative with radiotherapy may provide a vigorous repertoire to alleviate the tumor encumbrance.Thence,we design a three-pronged platinum@polymer-catechol nanobraker to deliver mTOR inhibitor TAK228 and anti-PD-L1 antibody(aPD-L1)for impeding the melanoma-PD-1-driven aggression and maximizing the melanoma eradication.The aPD-L1 collaborated with TAK228 restrains melanoma cell-intrinsic PD-1:PD-L1 tumorigenic interaction via blocking melanoma-PD-L1 ligand and the melanoma-PD-1 receptor-driven mTOR signaling;corresponding downregulation of mTOR downstream protumorigenic cellular MYC and proangiogenic hypoxia-inducible factor 1-alpha is conducive to preventing tumorigenesis and angiogenesis,respectively.Further,high-Z metal platinum sensitizing TAK228-enhanced radiotherapy confers the nanobraker on remarkable tumoricidal efficacy.Hereto,the customized three-pronged nanobrakers efficiently suppress melanoma tumorigenesis and angiogenesis concomitant with the amplification of radiotherapeutic efficacy.Such an ingenious tactic may provide substantial benefits to clinical melanoma patients.
基金
This work was supported by the National Natural Science Foundation of China(NSFC 32171318 and 32101069)
the Faculty of Health Sciences,University of Macao,the Science and Technology Development Fund,Macao SAR(File no.0109/2018/A3,0011/2019/AKP,0113/2019/A2,0103/2021/A,and 0002/2021/AKP)
the Multi-Year Research Grant(MYRG)of University of Macao(File no.MYRG2022-00011-FHS)
Shenzhen Science and Technology Innovation Commission,Shenzhen-Hong Kong-Macao Science and Technology Plan C(No.SGDX20201103093600004).
