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Research Article

Spatially targeting of tumor-associated macrophages and cancer cells for suppression of spontaneously metastatic tumor

Minglu Zhou§, Dandan Xie§, Zhou Zhou, Lian Li, Yuan Huang ( )
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China

§ Minglu Zhou and Dandan Xie contributed equally to this work.

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Graphical Abstract

The liposomes functionalized with alanine-alanine-asparagine (AAN) peptide and loaded with regorafenib (AAN-Lip-Rego) accumulated at perivascular sites where the M2-type tumor-associated macrophages (M2-TAMs) located to repolarize M2-TAMs to M1-TAMs, while internalizing RGD modified with N-(2-hydroxypropyl) methacrylamide–doxorubicin (iRGD-HD) penetrated into deep site of tumor to attack cancer cells. As a result, iRGD-HD/AAN-Lip-Rego combination reversed the immunosuppressive tumor microenvironment and activated the T cell-mediated antitumor immune response to markedly inhibit the growth of orthotropic 4T1 tumors and the formation of spontaneous lung metastasis.

Abstract

The interaction between cancer cells and M2 tumor-associated macrophages (M2-TAMs) facilitates tumor growth and metastasis. However, cancer cells and M2-TAMs have different spatial distribution patterns, which requires distinct drug delivery strategies. Herein, based on different tumor-penetrating ability of nanocarriers, we developed a combinatory strategy that consists of a TAMs-targeting liposome (alanine-alanine-asparagine (AAN)-Lip-regorafenib (Rego)) and a cancer cells-targeting copolymer (internalizing RGD modified with N-(2-hydroxypropyl) methacrylamide-doxorubicin (iRGD-HD)). Our study confirmed AAN-Lip-Rego accumulated at perivascular sites where M2-TAM is located, while iRGD-HD penetrated into deep site of tumor to enter cancer cells. Thereafter, we found iRGD-HD induced cancer cells undergoing immunogenic cell death to enhance tumor infiltration of CD8+ T cells. Meanwhile, AAN-Lip-Rego efficiently repolarized TAMs from M2 into M1 to alleviate tumor immunosuppression, thus reviving CD8+ T cells. Moreover, the repolarization of TAMs led to dramatic downregulation of pro-metastatic factors expressed on cancer cells. As a result, such combinatory approach elicited robust antitumor immune responses and generated considerable anti-tumor and anti-metastasis efficacy to markedly inhibit primary tumor and spontaneous lung metastasis.

Keywords

spatial distributiontumor-associated macrophageimmunogenic cell deathanti-tumor immunitycancer metastasis

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Nano Research
Volume 15 Issue 4,
April 2022
Pages 3446-3457
DOI: 10.1007/s12274-021-3976-9
Cite this article:
Zhou M, Xie D, Zhou Z, et al. Spatially targeting of tumor-associated macrophages and cancer cells for suppression of spontaneously metastatic tumor. Nano Research, 2022, 15(4): 3446-3457. https://doi.org/10.1007/s12274-021-3976-9
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Received: 11 September 2021
Revised: 01 November 2021
Accepted: 02 November 2021
Published: 26 December 2021
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021
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