2. Academic Validation
  3. Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy

Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy

  • J Control Release. 2022 Nov 11;352:793-812. doi: 10.1016/j.jconrel.2022.11.004.
Zaigang Zhou 1,  Yu Liu 2,  Wei Song 3,  Xin Jiang 4,  Zaian Deng 5,  Wei Xiong 6,  Jianliang Shen 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 2 State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China.
  • 3 State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China; Department of Urology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha 410005, China.
  • 4 Department of Urology, The Third Xiangya Hospital of Central South University, Changsha 410013, China.
  • 5 College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, Guangdong 518118, China. Electronic address: dengzaian@sztu.edu.cn.
  • 6 Department of Urology, The Third Xiangya Hospital of Central South University, Changsha 410013, China. Electronic address: xiongweixymn@163.com.
  • 7 State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325027, China; Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325001, China. Electronic address: shenjl@wiucas.ac.cn.
PMID: 36343761 DOI: 10.1016/j.jconrel.2022.11.004
Abstract

As a promising Cancer treatment, photodynamic therapy (PDT) still achieved limited clinical success due to the severe hypoxia and programmed death ligand-1 (PD-L1) over-expressed immunosuppression tumor microenvironment. At present, few methods have been proven to solve these two defects simply and effectively by a single drug or nano-system simultaneously. To ameliorate this situation, we designed and constructed MB@Bu@MnO2 nanoparticles with two-step oxygen regulation ability and PD-1/PD-L1 axis cascade-disruption capacity via a biomineralization method. In such a nanosystem, manganese dioxide albumin (MnO2@Alb) was used as the drug carrier, Butformin (Bu) as mitochondria-associated Oxidative Phosphorylation (OXPHOS) disruption agent with PD-L1 depression and oxygen reversion ability, and methylene blue (MB) as PDT drug with programmed cell death protein 1 (PD-1) inhibition capacity. Owing to the tumor-responsive capacity of MB@Bu@MnO2 nanoparticles, Bu and MB were selectively delivered and released in tumors. Then, the tumor hypoxia was dramatically reversed by Bu inhibited oxygen consumption, and MnO2 improved oxygen generation. Following this, the Reactive Oxygen Species (ROS) generation was enhanced by MB@Bu@MnO2 nanoparticles mediated PDT owing to the reversed tumor hypoxia. Furthermore, the immunosuppression microenvironment was also obviously reversed by MB@Bu@MnO2 nanoparticles enhanced immunogenic cell death (ICD) and PD-1/PD-L1 axis cascade-disruption, which then enhanced T cell infiltration and improved its tumor cell killing ability. Finally, the growth of solid tumors was significantly depressed by MB@Bu@MnO2 nanoparticles mediated PDT. All in all, this well-designed nanosystem could solve the defects of traditional PDT via PD-1/PD-L1 axis dual disruption and reversing tumor hypoxia by two-step oxygen regulation.

Keywords

Butformin; Hypoxia; Methylene blue; Mitochondrial oxidative phosphorylation; Photodynamic immunotherapy; Programmed death ligand-1.

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