Surface Molecularly Engineered Mitochondria Conduct Immunophenotype Repolarization of Tumor‐Associated Macrophages to Potentiate Cancer Immunotherapy

Author:

Zhang Cai‐Ju12,Li Jia‐Mi34,Xu Dan5,Wang Dan‐Dan3,Qi Ming‐Hui3,Chen Feng2,Wu Bo1,Deng Kai1ORCID,Huang Shi‐Wen36

Affiliation:

1. Department of Radiology, Zhongnan Hospital of Wuhan University Wuhan University Wuhan 430071 China

2. Department of Radiology Hainan Hospital Affiliated to Hainan Medical University Hainan 570311 China

3. Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry Wuhan University Wuhan 430072 China

4. Department of Radiology Renmin Hospital of Wuhan University Jiefang Road 238,Wuchang District Wuhan Hubei 430060 China

5. Department of Nuclear Medicine, Zhongnan Hospital of Wuhan University Wuhan University Wuhan 430071 China

6. Department of Orthopedic Trauma and Microsurgery Zhongnan Hospital of Wuhan University Wuhan 430071 China

Abstract

AbstractReprogramming tumor‐associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF‐κB p65, MAPK p38 and JNK by glycolysis‐mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti‐PD‐L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future.

Funder

National Natural Science Foundation of China

Publisher

Wiley

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