A Smart Nanomedicine Unleashes a Dual Assault of Glucose Starvation and Cuproptosis to Supercharge αPD-L1 Therapy

Sep 21, 2026

Uploaded by Aurelia

A glucose- and copper-metry-targeted intelligent biomimetic nanodelivery system is developed to improve anti-PD-L1 therapy outcomes in lung cancer. By camouflaging lung cancer cell membranes onto glucose oxidase-loaded Cu-LDHs, the system synergistically regulates PD-L1 expression through self-amplified cascade reactions, inducing cuproptosis and PD-L1 upregulation. In LLC lung tumor-bearing mice, it shows tumor targeting, biosafety, and strong anti-tumor efficacy, and combination dosing sensitizes αPD-L1 treatment to suppress both subcutaneous growth and lung metastasis.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Immunotherapy and PD-L1 limitations

Rationale for metabolism-targeted combination strategies

Glucose starvation via glucose oxidase

Role of TCA cycle and copper in cancer cell death

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) A Smart Nanomedicine Unleashes a Dual Assault of Glucose Starvation and Cuproptosis to Supercharge 􀀂PD-L1 Therapy Yiming Xu, Yuan Wu, Xinjie Zheng, Dongxue Wang, Hangqi Ni, Weiyu Chen,* and Kai Wang* Combination therapy has become a promising strategy for promoting the outcomes of anti-programmed death ligand-1 (􀀂PD-L1) therapy in lung cancer. Among all, emerging strategies targeting cancer metabolism have shown great potency in treating cancers with immunotherapy. Here, alteration in glucose and copper metabolisms is found to synergistically regulate PD-L1 expression in lung cancer cells. Thus, an intelligent biomimetic nano-delivery system is synthesized by camouﬂaging lung cancer cell membranes onto glucose oxidase-loaded Cu-LDHs (CMGCL) for cancer metabolism targeted interference. Such novel nanomedicine is able to induce lung cancer cell cuproptosis and PD-L1 upregulation signiﬁcantly via self-ampliﬁed cascade reactions. Meanwhile, with a decent cancer cell membrane coating, CMGCL exhibited great biosafety, tumor-targeted eﬃciency and anti-tumor eﬀects in LLC lung tumor-bearing mice models. Additionally, a combination of CMGCL can sensitize the therapeutic eﬀects of 􀀂PD-L1, substantially promoting tumor inhibition in both subcutaneous and lung metastasis LLC-bearing mice models. Overall, these ﬁndings highlight the potential connections between glucose metabolism and cell cuproptosis, oﬀering a promising approach for treating lung cancer by integrating starvation, cuproptosis, and immunotherapy. 1. Introduction To date, lung cancer still contributes to most cancer-related deaths worldwide, with ≈2.4 million new diagnoses and 1.3 million fatalities reported annually.[1] Recently, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has garnered signiﬁcant attention due to the desirable therapeutic outcomes for most lung cancer patients. [2] For instance, the anti-programmed death ligand-1 (􀀂PD-L1) antibody, as one of the most widely used ICIs, has been approved for more than 20 types of solid tumors, including lung cancer. However, some patients respond poorly or generate resistance due to a shortage of PD-L1 expression and dysfunctional immune response within the tumor microenvironment (TME) . [2b,3] Moreover, similar to other traditional therapies (e.g., chemotherapy or radiotherapy), the accompanying side eﬀects, such as immunerelated adverse eﬀects (irAEs), also limit Y. Xu, X. Zheng, H. Ni, W. Chen, K. Wang Department of Respiratory and Critical Care Medicine Center for Oncology Medicine The Fourth Aﬃliated Hospital of School of Medicine and International School of Medicine International Institutes of Medicine Zhejiang University Yiwu 322000, China [E-mail:](E-mail: weiyuchen@zju.edu.cn)[ weiyuchen@zju.edu.cn](E-mail: weiyuchen@zju.edu.cn); [kaiw@zju.edu.cn](kaiw@zju.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202411378](https://doi.org/10.1002/advs.202411378)[ ](https://doi.org/10.1002/advs.202411378)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Y. Xu, X. Zheng, H. Ni, W. Chen, K. Wang Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer Yiwu 322000, China Y. Wu College of Jiyang Zhejiang A&F University Zhuji 311800, China D. Wang Department of Nuclear Medicine The Second Aﬃliated Hospital of Harbin Medical University Harbin 150000, China DOI: 10.1002/advs.202411378 Adv. Sci. 2025, 12, 2411378 2411378 (1 of 15) © 2024 The Author(s) . Advanced Science published by Wiley-VCH GmbH [www.advancedsciencenews.com](www.advancedsciencenews.com) [www.advancedscience.com](www.adv

FAQs

What is the main goal of this nanomedicine study?

To enhance the therapeutic outcomes of anti-PD-L1 treatment in lung cancer by linking glucose metabolism disruption and cuproptosis with immunotherapy.

How does the proposed system target cancer metabolism?

It uses a biomimetic nano-delivery platform that camouflages lung cancer cell membranes on glucose oxidase-loaded Cu-LDHs to interfere with glucose and copper metabolism in tumor cells.

What benefits are reported in animal tumor models when combining with αPD-L1 therapy?

Combination treatment with the nanomedicine sensitizes αPD-L1 effects, substantially improving tumor inhibition in both subcutaneous and lung metastasis LLC-bearing mice while maintaining biosafety.

Sep 21, 2026

Uploaded by Aurelia