Tumor Selective Metabolic Reprogramming as a Prospective PD-L1 Depression Strategy to Reactivate Immunotherapy

Yu Liu, Zaigang Zhou, Jiting Hou, Wei Xiong, Heejeong Kim, Jiashe Chen, Chunjuan Zheng, Xin Jiang, Juyoung Yoon, Jianliang Shen

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

Abstract

Currently, the role of the lysosome, endoplasmic reticulum, or dictyosome in the transcription and translation of programmed cell death ligand 1 (PD-L1) is well revealed, but the role and function of mitochondria in the PD-L1 expression in tumors is still not fully researched, making it hard to offer a novel PD-L1 regulation strategy. In this research, it is newly revealed that mitochondria oxidative phosphorylation (OXPHOS) depression can be used as an effective PD-L1 down-regulation method. To offer an ideal and high-effective tumor mitochondria-targeted OXPHOS depression nanosystem, IR-LND is prepared by conjugating mitochondria-targeted heptamethine cyanine dye IR-68 with mitochondrial complexes I and II depression agent lonidamine (LND), which then further self-assembled with albumin (Alb) to form IR-LND@Alb nanoparticles. By doing this, PD-L1 expression in tumors is selectively and effectively depressed by IR-LND@Alb nanoparticles. As expected, the anti-tumor efficacy of such a PD-L1 depression strategy is superior to conventional anti-PD-L1 monoclonal antibodies. Interestingly, IR-LND can also be served as a novel ideal promising photodynamic therapy (PDT) drug with self-oxygen and self-PD-L1 regulation capacity. All in all, this tumor-selective metabolic reprogramming platform to reactivate immunotherapy and sensitize for PDT effect, would open a new window for mitochondrial immunotherapy for cancer patients.

Original languageEnglish
Article number2206121
JournalAdvanced Materials
Volume34
Issue number41
DOIs
StatePublished - 13 Oct 2022

Bibliographical note

Funding Information:
This work was supported by the National Natural Science Foundation of China (82003697 and 21977081), the Zhejiang Provincial Natural Science of Foundation of China (LZ19H180001), and Wenzhou Medical University (KYYW201901). J.Y. thanks the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2022R1A2C3005420). J.S. acknowledges funding received from Zhejiang Qianjiang Talent Plan (QJD20020224). Ethical approval was granted by the Institutional Animal Care and Use Committee of Wenzhou Institute, University of Chinese Academy of Sciences (WIUCAS22040606).

Funding Information:
This work was supported by the National Natural Science Foundation of China (82003697 and 21977081), the Zhejiang Provincial Natural Science of Foundation of China (LZ19H180001), and Wenzhou Medical University (KYYW201901). J.Y. thanks the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2022R1A2C3005420). J.S. acknowledges funding received from Zhejiang Qianjiang Talent Plan (QJD20020224). Ethical approval was granted by the Institutional Animal Care and Use Committee of Wenzhou Institute, University of Chinese Academy of Sciences (WIUCAS22040606).

Publisher Copyright:
© 2022 Wiley-VCH GmbH.

Keywords

  • immunotherapy
  • mitochondria
  • photodynamic therapy
  • programmed death ligand-1
  • tumor targeting

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