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Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer

Author

Listed:
  • Xijiao Ren

    (Chongqing University)

  • Zhuo Cheng

    (Chongqing University)

  • Jinming He

    (Chongqing University)

  • Xuemei Yao

    (Chongqing University)

  • Yingqi Liu

    (Chongqing University)

  • Kaiyong Cai

    (Chongqing University)

  • Menghuan Li

    (Chongqing University)

  • Yan Hu

    (Chongqing University)

  • Zhong Luo

    (Chongqing University)

Abstract

Immune-checkpoint inhibitors (ICI) are promising modalities for treating triple negative breast cancer (TNBC). However, hyperglycolysis, a hallmark of TNBC cells, may drive tumor-intrinsic PD-L1 glycosylation and boost regulatory T cell function to impair ICI efficacy. Herein, we report a tumor microenvironment-activatable nanoassembly based on self-assembled aptamer-polymer conjugates for the targeted delivery of glucose transporter 1 inhibitor BAY-876 (DNA-PAE@BAY-876), which remodels the immunosuppressive TME to enhance ICI response. Poly β-amino ester (PAE)-modified PD-L1 and CTLA-4-antagonizing aptamers (aptPD-L1 and aptCTLA-4) are synthesized and co-assembled into supramolecular nanoassemblies for carrying BAY-876. The acidic tumor microenvironment causes PAE protonation and triggers nanoassembly dissociation to initiate BAY-876 and aptamer release. BAY-876 selectively inhibits TNBC glycolysis to deprive uridine diphosphate N-acetylglucosamine and downregulate PD-L1 N-linked glycosylation, thus facilitating PD-L1 recognition of aptPD-L1 to boost anti-PD-L1 therapy. Meanwhile, BAY-876 treatment also elevates glucose supply to tumor-residing regulatory T cells (Tregs) for metabolically rewiring them into an immunostimulatory state, thus cooperating with aptCTLA-4-mediated immune-checkpoint inhibition to abolish Treg-mediated immunosuppression. DNA-PAE@BAY-876 effectively reprograms the immunosuppressive microenvironment in preclinical models of TNBC in female mice and provides a distinct approach for TNBC immunotherapy in the clinics.

Suggested Citation

  • Xijiao Ren & Zhuo Cheng & Jinming He & Xuemei Yao & Yingqi Liu & Kaiyong Cai & Menghuan Li & Yan Hu & Zhong Luo, 2023. "Inhibition of glycolysis-driven immunosuppression with a nano-assembly enhances response to immune checkpoint blockade therapy in triple negative breast cancer," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42883-2
    DOI: 10.1038/s41467-023-42883-2
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    1. Sahil Inamdar & Abhirami P. Suresh & Joslyn L. Mangal & Nathan D. Ng & Alison Sundem & Christopher Wu & Kelly Lintecum & Abhirami Thumsi & Taravat Khodaei & Michelle Halim & Nicole Appel & Madhan Moha, 2023. "Rescue of dendritic cells from glycolysis inhibition improves cancer immunotherapy in mice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Qin Wu & Wail ba-alawi & Genevieve Deblois & Jennifer Cruickshank & Shili Duan & Evelyne Lima-Fernandes & Jillian Haight & Seyed Ali Madani Tonekaboni & Anne-Marie Fortier & Hellen Kuasne & Trevor D. , 2020. "GLUT1 inhibition blocks growth of RB1-positive triple negative breast cancer," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    3. Roberta Zappasodi & Inna Serganova & Ivan J. Cohen & Masatomo Maeda & Masahiro Shindo & Yasin Senbabaoglu & McLane J. Watson & Avigdor Leftin & Rachana Maniyar & Svena Verma & Matthew Lubin & Myat Ko , 2021. "CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours," Nature, Nature, vol. 591(7851), pages 652-658, March.
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