Synergistic fluvastatin-nanotherapy suppresses DEPDC1-associated glycolysis and exosomal CCL2 to modulate the immune microenvironment in lung adenocarcinoma.
9 affiliations
- 1Guangzhou Medical University, Guangzhou, 511436, Guangdong Province, China.
- 2Guangzhou National Laboratory, Guangzhou, 510005, Guangdong Province, China.
- 3Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China.
- 4Guangxi Colleges and Universities Key Laboratory of Natural and Biomedical Polymer Materials, College of Materials Science and Engineering, Guilin University of Technology, Guilin, 541004, China.
- 5Cancer Center, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
- 6Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau, SAR, China.
- 7Guangdong Provincial Key Laboratory of Advanced Biomaterials, Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518055, China. [email protected].
- 8Guangzhou Medical University, Guangzhou, 511436, Guangdong Province, China. [email protected].
- 9Guangzhou National Laboratory, Guangzhou, 510005, Guangdong Province, China. [email protected].
Abstract
Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer, is characterized by high incidence, poor prognosis, limited therapeutic efficacy. Glycolysis-high LUAD is associated with aggressive tumor behavior and immunosuppressive tumor microenvironment (TME) that broadly impairs anti-tumor immunity and therapeutic efficacy. Effective strategies targeting this metabolically aggressive phenotype are urgently needed. In this study, we developed a combination strategy that modulates DEPDC1-associated glycolysis by integrating fluvastatin (Fluv) with an integrin αVβ3-targeted photodynamic nanoplatform (cRGD-TPA-DCR-NP, with light irradiation; NPL), termed Fluv + NPL. Integrated multi-omics analyses, together with Western blotting and glycolytic rate (GlycoPER) measurements, demonstrated that Fluv + NPL suppressed DEPDC1-mediated NF-κB signaling, thereby inhibiting PI3K-AKT-mTOR pathway activity and reducing glycolytic metabolism in LUAD cells. Simultaneously, Fluv + NPL downregulated exosomal CCL2 levels and inhibited M2 macrophage polarization. In vivo studies further showed that Fluv + NPL effectively modulated the immune microenvironment of LUAD, as evidenced by enhanced M1 macrophage polarization, increased infiltration of effector T cells, and reduced M2 macrophage abundance, ultimately resulting in significant inhibition of LUAD growth. Collectively, our findings reveal an important role of DEPDC1 in linking glycolytic metabolism to immune regulation and establish Fluv + NPL as a promising therapeutic strategy that simultaneously suppresses glycolysis and enhances antitumor immunity through modulation of DEPDC1. These results provide new insights into glycolytic metabolism-immunity-based combination therapies for LUAD.
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BibTeX
@article{li2026synergistic,
title = {{Synergistic fluvastatin-nanotherapy suppresses DEPDC1-associated glycolysis and exosomal CCL2 to modulate the immune microenvironment in lung adenocarcinoma.}},
author = {Chunhua Li and Xingyu Lyu and Tianyi Kang and Xianming Zhang and Li Zhou and Yi Wang and Zhuocai Wei and Ying Huang and Changqi Yuan and Ziyue Zhang and Luyao Wei and Kai Li and Ming Dong},
journal = {Journal of nanobiotechnology},
year = {2026},
month = jul,
doi = {10.1186/s12951-026-04829-w},
url = {https://europepmc.org/article/MED/42958526},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Synergistic fluvastatin-nanotherapy suppresses DEPDC1-associated glycolysis and exosomal CCL2 to modulate the immune microenvironment in lung adenocarcinoma.
AU - Chunhua Li
AU - Xingyu Lyu
AU - Tianyi Kang
AU - Xianming Zhang
AU - Li Zhou
AU - Yi Wang
AU - Zhuocai Wei
AU - Ying Huang
AU - Changqi Yuan
AU - Ziyue Zhang
AU - Luyao Wei
AU - Kai Li
AU - Ming Dong
PY - 2026
DA - 2026/07/28
JO - Journal of nanobiotechnology
DO - 10.1186/s12951-026-04829-w
UR - https://europepmc.org/article/MED/42958526
AB - Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer, is characterized by high incidence, poor prognosis, limited therapeutic efficacy. Glycolysis-high LUAD is associated with aggressive tumor behavior and immunosuppressive tumor microenvironment (TME) that broadly impairs anti-tumor immunity and therapeutic efficacy. Effective strategies targeting this metabolically aggressive phenotype are urgently needed. In this study, we developed a combination strategy that modulates DEPDC1-associated glycolysis by integrating fluvastatin (Fluv) with an integrin αVβ3-targeted photodynamic nanoplatform (cRGD-TPA-DCR-NP, with light irradiation; NPL), termed Fluv + NPL. Integrated multi-omics analyses, together with Western blotting and glycolytic rate (GlycoPER) measurements, demonstrated that Fluv + NPL suppressed DEPDC1-mediated NF-κB signaling, thereby inhibiting PI3K-AKT-mTOR pathway activity and reducing glycolytic metabolism in LUAD cells. Simultaneously, Fluv + NPL downregulated exosomal CCL2 levels and inhibited M2 macrophage polarization. In vivo studies further showed that Fluv + NPL effectively modulated the immune microenvironment of LUAD, as evidenced by enhanced M1 macrophage polarization, increased infiltration of effector T cells, and reduced M2 macrophage abundance, ultimately resulting in significant inhibition of LUAD growth. Collectively, our findings reveal an important role of DEPDC1 in linking glycolytic metabolism to immune regulation and establish Fluv + NPL as a promising therapeutic strategy that simultaneously suppresses glycolysis and enhances antitumor immunity through modulation of DEPDC1. These results provide new insights into glycolytic metabolism-immunity-based combination therapies for LUAD.
SN - 1477-3155
ER -