Yu Baixue, Zhang Wei, Shao Zhouchuan, Chen Xiayun, Cen Yi, Liu Yibin, Chen Ying, Li Xinxuan, Liang Ziqi, Li Shiying, Chen Xiaoyuan
The Fifth Affiliated Hospital, Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, The NMPA and State Key Laboratory of Respiratory Disease, The School of Pharmaceutical Sciences, Guangzhou Medical University Guangzhou 511436 P. R. China
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore 119074 Singapore
Chem Sci. 2025 May 1. doi: 10.1039/d5sc01953b.
The activation of antitumor immunity through strategically designed nanomedicine presents a promising approach to overcome the limitations of conventional cancer therapies. In this work, bioinformatic analysis found an abnormal poly(ADP-ribose) polymerase-1 (PARP-1) expression in breast cancer, linked to the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) pathway and immune suppression. PARP-1 inhibitor screening revealed olaparib (Ola) as a promising candidate, enhancing DNA damage and potentiating the immunotherapeutic response. Consequently, a self-promoted tumor-targeting nanomedicine (designated as PN-Ola) was proposed to activate STING-driven antitumor immunity through photodynamic DNA damage and PARP inhibition. PN-Ola was composed of a programmed death-ligand 1 (PD-L1) targeting amphiphilic peptide-photosensitizer conjugate (C-K(PpIX)-WHRSYYTWNLNT), which effectively encapsulates Ola. Notably, PN-Ola demonstrated selective accumulation in tumor cells that overexpress PD-L1, while concurrently enhancing PD-L1 expression, thereby establishing a self-promoting mechanism for improved drug accumulation within tumor cells. Meanwhile, the photodynamic therapy (PDT) effects of PN-Ola would result in oxidative DNA damage and subsequent accumulation of DNA fragments. Additionally, the PARP inhibition provided by PN-Ola disrupted the DNA repair pathways in tumor cells, leading to a boosted release of DNA fragments that further stimulated STING-driven antitumor immunity. The synergistic mechanism of PN-Ola effectively activates the immunotherapeutic response by enhancing T cell activation and infiltration, leading to the eradication of metastatic tumors without inducing side effects. This study presents a promising strategy to overcome targeting ligand heterogeneity while activating systemic antitumor immunity for the effective eradication of metastatic tumors.
通过精心设计的纳米药物激活抗肿瘤免疫为克服传统癌症治疗的局限性提供了一种有前景的方法。在这项工作中，生物信息学分析发现乳腺癌中聚（ADP - 核糖）聚合酶 -1（PARP -1）表达异常，这与环磷酸鸟苷 - 腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）通路及免疫抑制相关。PARP -1抑制剂筛选显示奥拉帕利（Ola）是一个有潜力的候选药物，可增强DNA损伤并增强免疫治疗反应。因此，提出了一种自我促进的肿瘤靶向纳米药物（命名为PN - Ola），通过光动力DNA损伤和PARP抑制来激活STING驱动的抗肿瘤免疫。PN - Ola由靶向程序性死亡配体1（PD - L1）的两亲性肽 - 光敏剂偶联物（C - K（PpIX）- WHRSYYTWNLNT）组成，它能有效包封Ola。值得注意的是，PN - Ola在过表达PD - L1的肿瘤细胞中表现出选择性积累，同时增强PD - L1表达，从而建立了一种自我促进机制以改善药物在肿瘤细胞内的积累。同时，PN - Ola的光动力疗法（PDT）效应会导致氧化性DNA损伤及随后DNA片段的积累。此外，PN - Ola提供的PARP抑制破坏了肿瘤细胞中的DNA修复途径，导致DNA片段的释放增加，进一步刺激STING驱动的抗肿瘤免疫。PN - Ola的协同机制通过增强T细胞活化和浸润有效激活免疫治疗反应，从而根除转移性肿瘤而不引起副作用。这项研究提出了一种有前景的策略，可在激活全身抗肿瘤免疫以有效根除转移性肿瘤的同时克服靶向配体的异质性。
