Selectively down-regulated PD-L1 by albumin-phenformin nanoparticles mediated mitochondrial dysfunction to stimulate tumor-specific immunological response for enhanced mild-temperature photothermal efficacy

Zaigang Zhou,Jiashe Chen,Chunjuan Zheng,Ning Jiang,Jianliang Shen,Ruirong Ye,Ruogu Qi,Yuanyuan Guo

doi:10.1186/s12951-021-01124-8

Abstract

BackgroundMild-temperature photothermal therapy (mild-PTT) has emerged as a highly promising antitumor strategy by triggering immunogenic cell death (ICD) to elicit both innate and adaptive immune responses for tumor control. However, mild-PTT still leads to the risk of tumor recurrence or metastasis because it could hardly completely eradicate tumors due to its impaired immunological efficacy owing to the enhanced PD-L1 expression in tumor cells after treatment.ResultsIn this study, we described a hydrogen peroxide (H2O2) responsive manganese dioxide mineralized albumin nanocomposite loading with mitochondria function inhibitor phenformin (PM) and near-infrared photothermal dye indocyanine green (ICG) by modified two-step biomineralization method. In combination with ICG induced mild-PTT and PM mediated mitochondria dysfunction, PD-L1 expression was obviously down-regulated and the generated immunological responses was able to effectively attack the remaining tumor cells. Meanwhile, the risk of tumor metastasis was effectively inhibited by reducing the expression of tumor invasion-related signal molecules (TGF-β and vimentin) after combining treatment.ConclusionSuch a strategy offers novel insight into the development of nanomedicine for mild-PTT as well as cancer immunotherapy, which can provide protection against tumor relapse post elimination of their initial and metastatic tumors.Graphical

Highlights

Developing effective cancer therapeutic strategies to selectively eliminate tumors with low toxicities are still urgently needed [1,2,3]
B The mechanism of enhanced mild-photothermal therapy (PTT) efficacy induced by indocyanine green (ICG)@PM@NP mediated PD-L1 expression down-regulation and tumor metastasis inhibition through effective mitochondrial function inhibition
The expression of two downstream tumor invasion-related signaling proteins of the AMPK pathway (TGF-β and vimentin), was effectively decreased by PM released from ICG@PM@ NP, resulting in lowered tumor metastasis risk and prolonged mice survival time that could not be realized by conventional mild-PTT alone (Figs. 4 and 8)

Summary

Introduction

Developing effective cancer therapeutic strategies to selectively eliminate tumors with low toxicities are still urgently needed [1,2,3]. Conventional clinical therapies including chemotherapy, surgery, and radiotherapy are still limited with some fatal defects, including enhanced tumor metastasis and some other severe adverse effects [4,5,6,7,8,9]. To address these challenges, cancer immunotherapy exhibited enormous promises has been evolved as the generation of therapeutic strategy. Mild-temperature photothermal therapy (mild-PTT) has emerged as a highly promising antitumor strategy by triggering immunogenic cell death (ICD) to elicit both innate and adaptive immune responses for tumor control. Mild-PTT still leads to the risk of tumor recurrence or metastasis because it could hardly completely eradicate tumors due to its impaired immunological efficacy owing to the enhanced PD-L1 expression in tumor cells after treatment

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Results

Discussion

Conclusion