Carrier-adjuvanted immunostimulator to boost photodynamicimmunotherapy by downregulating PD-L1 and impairing ATP hydrolysis  

载体辅助免疫刺激剂通过下调PD-L1和抑制ATP水解增强光动力免疫治疗

作　　者：Yi Cen Ying Chen Hua Cai Xinxuan Li Xiayun Chen Qianqian Liu Baixue Yu Yibin Liu Tao Wang Shiying Li 岑怡;陈颖;蔡华;李欣璇;陈霞云;刘倩倩;俞白雪;刘已斌;王涛;李仕颖(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,China;Graduate School,Guangzhou University of Chinese Medicine,Guangzhou 510006,China;Department of Pulmonary and Critical Care Medicine,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China)

机构地区：[1]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,China [2]Graduate School,Guangzhou University of Chinese Medicine,Guangzhou 510006,China [3]Department of Pulmonary and Critical Care Medicine,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China

出　　处：《Science China Materials》2025年第2期626-639,共14页中国科学(材料科学)(英文版)

基　　金：financially supported by the National Key R&D Program of China (2021YFD1800600);the National Natural Science Foundation of China (32371394);the Open Research Foundation of State Key Laboratory of Respiratory Diseases (SKLRD-OP-202204)。

摘　　要：Immune evasion behavior and immunosuppressive characteristics of tumor extensively impedethe immune initiation effect of therapy triggered immunogeniccell death (ICD). In this work, a carrier-adjuvantedimmunostimulator (designated as CoCeC) is developed toboost photodynamic immunotherapy by downregulatingprogrammed death ligand 1 (PD-L1) and impairing adenosinetriphosphate (ATP) hydrolysis. Among these, the crosslinkedchitosan oligosaccharide is applied as the drug carrier fordelivery of Ce6 and Ceritinib, which also serves as an immuneadjuvant to downregulate PD-L1. Meanwhile, the robustphotodynamic therapy (PDT) of CoCeC exhibits lethal toxicityagainst tumor cells to induce ICD and release damage-associated molecular patterns (DAMPs), which can also impairATP hydrolysis by blocking CD39. In vitro and in vivo resultsdemonstrate the robust therapeutic efficacy of CoCeC tosuppress primary tumor growth and activate a superior immune elimination against lung metastasis by amplifying theimmune initiation of ICD with the assistance of immune adjuvants.This work provides a self-adjuvanted strategy to enhance the immune response of therapy induced ICD, which ispromising to activate systemic antitumor immunity in consideration of the complicated immunosuppressive factors.肿瘤细胞存在免疫逃避和免疫抑制特性,极大削弱了免疫激活效应和抗肿瘤免疫疗效.本文开发了一种载体辅助免疫刺激剂(称为CoCeC),通过下调肿瘤细胞程序性死亡配体1 (PD-L1)和抑制三磷酸腺苷(ATP)水解,实现肿瘤光动力免疫治疗.其中,交联的寡聚壳聚糖是递送二氢卟吩e6和色瑞替尼的药物载体,也是下调PD-L1的免疫佐剂,可抑制肿瘤细胞的免疫逃逸.同时,CoCeC的光动力疗法(PDT)能破坏肿瘤细胞,进而诱导肿瘤细胞发生免疫原性死亡(ICD)并释放损伤相关分子模式(DAMPs),阻断CD39抑制ATP水解为腺苷,从而抑制腺苷造成的肿瘤免疫抑制特性.体外和体内研究结果表明,CoCeC能有效抑制原发性肿瘤的生长,并通过改善肿瘤免疫原性、阻断肿瘤免疫逃逸和逆转肿瘤免疫抑制特性,实现光动力免疫激活和肺转移瘤免疫治疗的目的.这种载体自佐剂策略为纳米药物理性设计提供了新方法,并为逆转多重肿瘤免疫抑制特性和激活抗肿瘤免疫治疗提供了新思路.

关 键 词：photodynamic therapy PD-L1 downregulation immunogenic cell death CD39 antitumor immunity 

分 类 号：R730.51[医药卫生—肿瘤]