Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization

Siyue Zhang; Fangyuan Xie; Kaichun Li; He Zhang; You Yin; Yuan Yu; Guangzhao Lu; Shihao Zhang; Yan Wei; Ke Xu; Yan Wu; Hong Jin; Lan Xiao; Leilei Bao; Can Xu; Yulin Li; Ying Lu; Jie Gao

doi:10.1016/j.apsb.2022.02.008

Gold nanoparticle-directed autophagy intervention for antitumor immunotherapy via inhibiting tumor-associated macrophage M2 polarization

Acta Pharm Sin B. 2022 Jul;12(7):3124-3138. doi: 10.1016/j.apsb.2022.02.008. Epub 2022 Feb 16.

Authors

Siyue Zhang^{1

2

3

4}, Fangyuan Xie^{1

5}, Kaichun Li⁶, He Zhang¹, You Yin⁷, Yuan Yu¹, Guangzhao Lu¹, Shihao Zhang⁸, Yan Wei³, Ke Xu³, Yan Wu⁹, Hong Jin¹⁰, Lan Xiao¹¹, Leilei Bao⁵, Can Xu¹², Yulin Li^{8

13}, Ying Lu¹, Jie Gao^{2

3}

Affiliations

¹ Department of Pharmacy, Naval Medical University, Shanghai 200433, China.
² Changhai Clinical Research Unit, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
³ Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
⁴ Unit for Drug and Instrument Supervision and Inspection of Wuxi Joint Logistic Support Center, Nanjing 210000, China.
⁵ Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai 200433, China.
⁶ Department of Oncology, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai 200434, China.
⁷ Department of Neurology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
⁸ Key Laboratory for Ultrafine Materials of Ministry of Education, Engineering Research Center for Biomedical Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai 200237, China.
⁹ Department of Biomaterial, College of Life Sciences, Mudanjiang Medical University, Mudanjiang 157011, China.
¹⁰ Department of Laboratory Medicine, Hongqi Hospital, Mudanjiang Medical College, Mudanjiang 157011, China.
¹¹ Centre for Biomedical Technologies, Queensland University of Technology, Brisbane QLD 4000, Australia.
¹² Department of Gastroenterology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, China.
¹³ Wenzhou Institute of Shanghai University, Wenzhou 325000, China.

Abstract

Tumor-associated macrophages (TAMs), one of the dominating constituents of tumor microenvironment, are important contributors to cancer progression and treatment resistance. Therefore, regulation of TAMs polarization from M2 phenotype towards M1 phenotype has emerged as a new strategy for tumor immunotherapy. Herein, we successfully initiated antitumor immunotherapy by inhibiting TAMs M2 polarization via autophagy intervention with polyethylene glycol-conjugated gold nanoparticles (PEG-AuNPs). PEG-AuNPs suppressed TAMs M2 polarization in both in vitro and in vivo models, elicited antitumor immunotherapy and inhibited subcutaneous tumor growth in mice. As demonstrated by the mRFP-GFP-LC3 assay and analyzing the autophagy-related proteins (LC3, beclin1 and P62), PEG-AuNPs induced autophagic flux inhibition in TAMs, which is attributed to the PEG-AuNPs induced lysosome alkalization and membrane permeabilization. Besides, TAMs were prone to polarize towards M2 phenotype following autophagy activation, whereas inhibition of autophagic flux could reduce the M2 polarization of TAMs. Our results revealed a mechanism underlying PEG-AuNPs induced antitumor immunotherapy, where PEG-AuNPs reduce TAMs M2 polarization via induction of lysosome dysfunction and autophagic flux inhibition. This study elucidated the biological effects of nanomaterials on TAMs polarization and provided insight into harnessing the intrinsic immunomodulation capacity of nanomaterials for effective cancer treatment.

Keywords: Autophagy flux; Cancer therapy; Gold nanoparticles; Lysosomal damage; M2 macrophage; Macrophage polarization; Nanomaterials; Tumor-associated macrophages.