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介孔锰纳米载体靶向递送二甲双胍以共同激活STING通路，克服免疫治疗耐药性。

Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance.

作者信息

Dou Yuanyao, Zheng Jie, Kang Jun, Wang Liping, Huang Daijuan, Liu Yihui, He Chao, Lin Caiyu, Lu Conghua, Wu Di, Han Rui, Li Li, Tang Liling, He Yong

机构信息

Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China.

Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China.

出版信息

iScience. 2024 May 30;27(7):110150. doi: 10.1016/j.isci.2024.110150. eCollection 2024 Jul 19.

DOI:10.1016/j.isci.2024.110150
PMID:39040065
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11261061/
Abstract

Targeting the stimulator of interferon genes (STING) pathway is a promising strategy to overcome primary resistance to immune checkpoint inhibitors in non-small cell lung cancer with the STK11 mutation. We previously found metformin enhances the STING pathway and thus promotes immune response. However, its low concentration in tumors limits its clinical use. Here, we constructed high-mesoporous Mn-based nanocarrier loading metformin nanoparticles (Mn-MSN@Met-M NPs) that actively target tumors and respond to release higher concentration of Mn ions and metformin. The NPs significantly enhanced the T cells to kill lung cancer cells with the STK11 mutant. The mechanism shows that enhanced STING pathway activation promotes STING, TBKI, and IRF3 phosphorylation through Mn ions and metformin release from NPs, thus boosting type I interferon production. , NPs in combination with a PD-1 inhibitor effectively decreased tumor growth. Collectively, we developed a Mn-MSN@Met-M nanoactivator to intensify immune activation for potential cancer immunotherapy.

摘要

靶向干扰素基因刺激物（STING）通路是克服STK11突变的非小细胞肺癌对免疫检查点抑制剂原发性耐药的一种有前景的策略。我们之前发现二甲双胍可增强STING通路，从而促进免疫反应。然而，其在肿瘤中的低浓度限制了其临床应用。在此，我们构建了负载二甲双胍纳米颗粒的高介孔锰基纳米载体（Mn-MSN@Met-M NPs），其可主动靶向肿瘤并响应释放更高浓度的锰离子和二甲双胍。这些纳米颗粒显著增强了T细胞对携带STK11突变的肺癌细胞的杀伤作用。机制表明，增强的STING通路激活通过纳米颗粒释放的锰离子和二甲双胍促进STING、TBKI和IRF3磷酸化，从而促进I型干扰素的产生。此外，纳米颗粒与PD-1抑制剂联合使用可有效抑制肿瘤生长。总体而言，我们开发了一种Mn-MSN@Met-M纳米激活剂以增强免疫激活，用于潜在的癌症免疫治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/21e77999f39d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/8779a075632b/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/e10132fb9bf7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/82e5c2cdf39f/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/d9210198a966/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/e5e28b524e18/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/bb535b0d8156/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/7293176b2cff/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/21e77999f39d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/8779a075632b/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/e10132fb9bf7/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/82e5c2cdf39f/sc1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/d9210198a966/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/e5e28b524e18/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/bb535b0d8156/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/7293176b2cff/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bc2b/11261061/21e77999f39d/gr6.jpg

相似文献

[1]
Mesoporous manganese nanocarrier target delivery metformin for the co-activation STING pathway to overcome immunotherapy resistance.

iScience. 2024-5-30

[2]
Metformin Combining PD-1 Inhibitor Enhanced Anti-Tumor Efficacy in Mutant Lung Cancer Through AXIN-1-Dependent Inhibition of STING Ubiquitination.

Front Mol Biosci. 2022-2-23

[3]
Manganese-Based Nanoactivator Optimizes Cancer Immunotherapy Enhancing Innate Immunity.

ACS Nano. 2020-4-28

[4]
Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy.

Cell Res. 2020-11

[5]
Combine and conquer: manganese synergizing anti-TGF-β/PD-L1 bispecific antibody YM101 to overcome immunotherapy resistance in non-inflamed cancers.

J Hematol Oncol. 2021-9-15

[6]
Responsive manganese-based nanoplatform amplifying cGAS-STING activation for immunotherapy.

Biomater Res. 2023-4-15

[7]
Potent STING activation stimulates immunogenic cell death to enhance antitumor immunity in neuroblastoma.

J Immunother Cancer. 2020-3

[8]
Enhancing Dendritic Cell Activation Through Manganese-Coated Nanovaccine Targeting the cGAS-STING Pathway.

Int J Nanomedicine. 2024

[9]
Metal coordination nanotheranostics mediated by nucleoside metabolic inhibitors potentiate STING pathway activation for cancer metalloimmunotherapy.

J Control Release. 2024-6

[10]
Mn-phenolic networks as synergistic carrier for STING agonists in tumor immunotherapy.

Mater Today Bio. 2024-3-11

引用本文的文献

[1]
Progress Update on STING Agonists as Vaccine Adjuvants.

Vaccines (Basel). 2025-3-31

[2]
Manganese-Based Nanotherapeutics for Targeted Treatment of Breast Cancer.

ACS Appl Bio Mater. 2025-5-19

[3]
Bibliometric analysis of metformin as an immunomodulator (2013-2024).

Front Immunol. 2025-1-8

[4]
Metformin-based nanomedicines for reprogramming tumor immune microenvironment.

Theranostics. 2025-1-1

本文引用的文献

[1]
Polydopamine Nanostructure-Enhanced Water Interaction with pH-Responsive Manganese Sulfide Nanoclusters for Tumor Magnetic Resonance Contrast Enhancement and Synergistic Ferroptosis-Photothermal Therapy.

ACS Nano. 2024-1-30

[2]
Metformin Reprograms Tryptophan Metabolism to Stimulate CD8+ T-cell Function in Colorectal Cancer.

Cancer Res. 2023-7-14

[3]
Metformin improves cancer immunotherapy by directly rescuing tumor-infiltrating CD8 T lymphocytes from hypoxia-induced immunosuppression.

J Immunother Cancer. 2023-5

[4]
A manganese-phenolic network platform amplifying STING activation to potentiate MRI guided cancer chemo-/chemodynamic/immune therapy.

Biomater Sci. 2023-5-30

[5]
Unlocking the promise of systemic STING agonist for cancer immunotherapy.

J Control Release. 2023-5

[6]
Manganese potentiates lipopolysaccharide-induced innate immune responses and septic shock.

Int J Biol Macromol. 2023-3-1

[7]
Fucoidan-ferulic acid nanoparticles alleviate cisplatin-induced acute kidney injury by inhibiting the cGAS-STING pathway.

Int J Biol Macromol. 2022-12-31

[8]
Metformin Combining PD-1 Inhibitor Enhanced Anti-Tumor Efficacy in Mutant Lung Cancer Through AXIN-1-Dependent Inhibition of STING Ubiquitination.

Front Mol Biosci. 2022-2-23

[9]
Metformin Bicarbonate-Mediated Efficient RNAi for Precise Targeting of Deficiency in Colon and Rectal Cancers.

Nano Today. 2022-4

[10]
Cell membrane coating integrity affects the internalization mechanism of biomimetic nanoparticles.

Nat Commun. 2021-9-30

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