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  3. A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy

A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy

  • Biomaterials. 2022 May;284:121533. doi: 10.1016/j.biomaterials.2022.121533.
Zan Dai 1,  Qiaoyun Wang 1,  Jie Tang 2,  Rui Qu 3,  Min Wu 3,  Haoze Li 3,  Yannan Yang 1,  Xu Zhen 4,  Chengzhong Yu 5
Affiliations

Affiliations

  • 1 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
  • 2 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia. Electronic address: j.tang3@uq.edu.au.
  • 3 Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210093, PR China.
  • 4 Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210093, PR China. Electronic address: zhenxu@nju.edu.cn.
  • 5 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia; School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, PR China. Electronic address: c.yu@uq.edu.au.
PMID: 35462304 DOI: 10.1016/j.biomaterials.2022.121533
Abstract

Adenosine and lactate accumulated in tumor microenvironment are two major causes of immunosuppression, their concurrent downregulation holds promise in effective Cancer Immunotherapy, but remains challenging. Here, a sub-6 nm MnFe2O4 conjugated with dichloroacetic acid (DCA) nanoparticle is developed to modulate tumor glucose metabolism and ATP catabolism for reversing the tumor immunosuppressive microenvironment. The ultrasmall MnFe2O4-DCA nanoparticle can efficiently enter mitochondria and supply oxygen, improving the bioactivity of DCA to regulate glucose metabolism and reduce lactate production CA. 100 times higher than free DCA itself. Moreover, this design significantly downregulates CD39 and CD73 expression than DCA or MnFe2O4 alone, which consequently decreases the extracellular ATP catabolism. The concurrent regulation of glucose metabolism and ATP catabolism leads to increased immunostimulatory ATP level and decreased immunosuppressive adenosine and lactate levels in tumor microenvironment, eventually amplified dendritic cells maturation, enhanced cytotoxic T lymphocyte response, and improved Cancer Immunotherapy efficacy.

Keywords

ATP catabolism; Glucose metabolism; Mitochondrial entry; Tumor immunosuppressive microenvironment; Ultrasmall nanocomposite.

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