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Nano Research 2023, 16(1): 771-781 https://doi.org/10.1007/s12274-022-4645-3
Research Article | Issue | Published: 05 August 2022

Immune microenvironment-reshaping Au@Bi2Te3 nanoparticles for spectral computed tomography/photoacoustic imaging-guided synergetic photo/radio/immunotherapy

Show Author's Information Kai Zhu1,2,§,  Zede Wu1,2,§,  Qiuyu Li2,  Meirong Hou1,2,  Honglei Hu1,2,  Shuting Zheng1,2,  Li Qi3,  Yikai Xu1( ),  Chenggong Yan1,4( ),  Bingxia Zhao2,5( )
Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Guangdong Provincial Key Laboratory of Medical Image Processing, Guangdong Province Engineering Laboratory for Medical Imaging and Diagnostic Technology, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
Experimental Education/Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China

§ Kai Zhu and Zede Wu contributed equally to this work.

Keywords:
immunotherapy, hypoxia, immunogenic cell death, radioresistance, programmed cell death-ligand 1 (PD-L1), spectral computed tomography (CT)
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Zhu K, Wu Z, Li Q, et al. Immune microenvironment-reshaping Au@Bi2Te3 nanoparticles for spectral computed tomography/photoacoustic imaging-guided synergetic photo/radio/immunotherapy. Nano Research, 2023, 16(1): 771-781. https://doi.org/10.1007/s12274-022-4645-3
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Abstract Full text Electronic supplementary material About this article

Radiotherapy (RT) mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death (ICD), which releases damaged-associated molecular patterns and generates “eat me” signals for the innate immune system to modulate the immunogenicity. However, tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction. Herein, Au@Bi2Te3-polyethylene glycol (PEG) was rationally constructed as theranostic nanozymes for mild photothermal therapy, tumor hypoxia modulation, and RT adjuvant cancer immunotherapy. The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species (ROS) generation, but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1 (PD-L1) to unleash immune-enhancing T cells. Moreover, Au@Bi2Te3-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy + RT to inhibit the tumor immune escape and improve antitumor immune response. Increased amounts of CD4+ and CD8+ T cells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors. Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle (NP) accumulation and oxygenation status at tumor sites. Collectively, Au@Bi2Te3-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mild-photothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.


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Abstract
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Electronic supplementary material
About this article

Immune microenvironment-reshaping Au@Bi2Te3 nanoparticles for spectral computed tomography/photoacoustic imaging-guided synergetic photo/radio/immunotherapy

Show Author's information Kai Zhu1,2,§, Zede Wu1,2,§, Qiuyu Li2, Meirong Hou1,2, Honglei Hu1,2, Shuting Zheng1,2, Li Qi3, Yikai Xu1( ), Chenggong Yan1,4( ), Bingxia Zhao2,5( )
Department of Medical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Guangzhou Key Laboratory of Tumor Immunology Research, Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
Guangdong Provincial Key Laboratory of Medical Image Processing, Guangdong Province Engineering Laboratory for Medical Imaging and Diagnostic Technology, School of Biomedical Engineering, Southern Medical University, Guangzhou 510515, China
Guangdong Provincial Key Laboratory of Shock and Microcirculation, Guangzhou 510515, China
Experimental Education/Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China

§ Kai Zhu and Zede Wu contributed equally to this work.

Abstract

Radiotherapy (RT) mediated tumor immunogenicity offers an opportunity for simultaneous RT and immunotherapy via immunogenic cell death (ICD), which releases damaged-associated molecular patterns and generates “eat me” signals for the innate immune system to modulate the immunogenicity. However, tumor hypoxia significantly reduces the therapeutic efficacy of RT and hampers its mediation of ICD induction. Herein, Au@Bi2Te3-polyethylene glycol (PEG) was rationally constructed as theranostic nanozymes for mild photothermal therapy, tumor hypoxia modulation, and RT adjuvant cancer immunotherapy. The tumor-specific production of oxygen could not only augment the effects of RT by enhanced reactive oxygen species (ROS) generation, but also reduce hypoxia-related cytokines and downregulate programmed cell death-ligand 1 (PD-L1) to unleash immune-enhancing T cells. Moreover, Au@Bi2Te3-PEG could act as an immune-blocking inhibitor by efficient ICD induction with the combination of mild-photothermal therapy + RT to inhibit the tumor immune escape and improve antitumor immune response. Increased amounts of CD4+ and CD8+ T cells and elevated levels of cytokines could be observed that eventually led to effective post-medication inhibition of primary and abscopal tumors. Spectral computed tomography/photoacoustic imaging allowed noninvasive and real-time tracking of nanoparticle (NP) accumulation and oxygenation status at tumor sites. Collectively, Au@Bi2Te3-PEG NPs could serve as effective theranostic nanoregulators with remarkable synergistic mild-photothermal/RT/immunotherapy effects that helped reshape the immune microenvironment and had remarkable molecular imaging properties.

Keywords: immunotherapy, hypoxia, immunogenic cell death, radioresistance, programmed cell death-ligand 1 (PD-L1), spectral computed tomography (CT)

References(40)

[1]

Sharma, P.; Hu-Lieskovan, S.; Wargo, J. A.; Ribas, A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017, 168, 707–723.
DOI Google Scholar
[2]

Zhu, L. P.; Liu, J.; Zhou, G. Y.; Liu, T. M.; Dai, Y. L.; Nie, G. J.; Zhao, Q. Remodeling of tumor microenvironment by tumor-targeting nanozymes enhances immune activation of CAR T cells for combination therapy. Small 2021, 17, 2102624.
DOI Google Scholar
[3]

Song, C.; Phuengkham, H.; Kim, Y. S.; Dinh, V. V.; Lee, I.; Shin, I. W.; Shin, H. S.; Jin, S. M.; Um, S. H.; Lee, H. et al. Syringeable immunotherapeutic nanogel reshapes tumor microenvironment and prevents tumor metastasis and recurrence. Nat. Commun. 2019, 10, 3745.
DOI Google Scholar
[4]

Guevara, M. L.; Persano, F.; Persano, S. Nano-immunotherapy: Overcoming tumour immune evasion. Semin. Cancer Biol. 2021, 69, 238–248.
DOI Google Scholar
[5]

Baxevanis, C. N.; Fortis, S. P.; Perez, S. A. The balance between breast cancer and the immune system: Challenges for prognosis and clinical benefit from immunotherapies. Semin. Cancer Biol. 2021, 72, 76–89.
DOI Google Scholar
[6]

Wan, C. X.; Keany, M. P.; Dong, H.; Al-Alem, L. F.; Pandya, U. M.; Lazo, S.; Boehnke, K.; Lynch, K. N.; Xu, R.; Zarrella, D. T. et al. Enhanced efficacy of simultaneous PD-1 and PD-L1 immune checkpoint blockade in high-grade serous ovarian cancer. Cancer Res. 2021, 81, 158–173.
DOI Google Scholar
[7]

Vranic, S.; Cyprian, F. S.; Gatalica, Z.; Palazzo, J. PD-L1 status in breast cancer: Current view and perspectives. Semin. Cancer Biol. 2021, 72, 146–154.
DOI Google Scholar
[8]

Mpekris, F.; Panagi, M.; Voutouri, C.; Martin, J. D.; Samuel, R.; Takahashi, S.; Gotohda, N.; Suzuki, T.; Papageorgis, P.; Demetriou, P. et al. Normalizing the microenvironment overcomes vessel compression and resistance to nano-immunotherapy in breast cancer lung metastasis. Adv. Sci. 2021, 8, 2001917.
DOI Google Scholar
[9]

Salas-Benito, D.; Pérez-Gracia, J. L.; Ponz-Sarvisé, M.; Rodriguez-Ruiz, M. E.; Martínez-Forero, I.; Castañón, E.; López-Picazo, J. M.; Sanmamed, M. F.; Melero, I. Paradigms on immunotherapy combinations with chemotherapy. Cancer Discov. 2021, 11, 1353–1367.
DOI Google Scholar
[10]

Tang, T. Y.; Huang, X.; Zhang, G.; Hong, Z. T.; Bai, X. L.; Liang, T. B. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Sig. Transduct. Target. Ther. 2021, 6, 72.
DOI Google Scholar
[11]

Cousin, N.; Cap, S.; Dihr, M.; Tacconi, C.; Detmar, M.; Dieterich, L. C. Lymphatic PD-L1 expression restricts tumor-specific CD8+ T-cell responses. Cancer Res. 2021, 81, 4133–4144.
DOI Google Scholar
[12]

Noman, M. Z.; Desantis, G.; Janji, B.; Hasmim, M.; Karray, S.; Dessen, P.; Bronte, V.; Chouaib, S. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014, 211, 781–790.
DOI Google Scholar
[13]

Yu, M.; Duan, X. H.; Cai, Y. J.; Zhang, F.; Jiang, S. Q.; Han, S. S.; Shen, J.; Shuai, X. T. Multifunctional nanoregulator reshapes immune microenvironment and enhances immune memory for tumor immunotherapy. Adv. Sci. 2019, 6, 1900037.
DOI Google Scholar
[14]

Qi, J.; Jin, F. Y.; Xu, X. L.; Du, Y. Z. Combination cancer immunotherapy of nanoparticle-based immunogenic cell death inducers and immune checkpoint inhibitors. Int. J. Nanomed. 2021, 16, 1435–1456.
DOI Google Scholar
[15]

Zheng, P.; Ding, B. B.; Jiang, Z. Y.; Xu, W. G.; Li, G.; Ding, J. X.; Chen, X. S. Ultrasound-augmented mitochondrial calcium ion overload by calcium nanomodulator to induce immunogenic cell death. Nano Lett. 2021, 21, 2088–2093.
DOI Google Scholar
[16]

Tang, H. L.; Xu, X. J.; Chen, Y. X.; Xin, H. H.; Wan, T.; Li, B. W.; Pan, H. M.; Li, D.; Ping, Y. Reprogramming the tumor microenvironment through second-near-infrared-window photothermal genome editing of PD-L1 mediated by supramolecular gold nanorods for enhanced cancer immunotherapy. Adv. Mater. 2021, 33, 2006003.
DOI Google Scholar
[17]

Obeid, M.; Tesniere, A.; Ghiringhelli, F.; Fimia, G. M.; Apetoh, L.; Perfettini, J. L.; Castedo, M.; Mignot, G.; Panaretakis, T.; Casares, N. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 2007, 13, 54–61.
DOI Google Scholar
[18]

Zhou, F. Y.; Feng, B.; Yu, H. J.; Wang, D. G.; Wang, T. T.; Ma, Y. T.; Wang, S. L.; Li, Y. P. Tumor microenvironment-activatable prodrug vesicles for nanoenabled cancer chemoimmunotherapy combining immunogenic cell death induction and CD47 blockade. Adv. Mater. 2019, 31, 1805888.
DOI Google Scholar
[19]

Choi, B.; Choi, H.; Yu, B.; Kim, D. H. Synergistic local combination of radiation and anti-programmed death ligand 1 immunotherapy using radiation-responsive splintery metallic nanocarriers. ACS Nano 2020, 14, 13115–13126.
DOI Google Scholar
[20]

Donlon, N. E.; Power, R.; Hayes, C.; Reynolds, J. V.; Lysaght, J. Radiotherapy, immunotherapy, and the tumour microenvironment: Turning an immunosuppressive milieu into a therapeutic opportunity. Cancer Lett. 2021, 502, 84–96.
DOI Google Scholar
[21]

Zhang, C. Y.; Yan, L.; Gu, Z. J.; Zhao, Y. L. Strategies based on metal-based nanoparticles for hypoxic-tumor radiotherapy. Chem. Sci. 2019, 1, 6932–6943.
DOI Google Scholar
[22]

Zhang, Q. H.; Chen, J. W.; Ma, M.; Wang, H.; Chen, H. R. A bioenvironment-responsive versatile nanoplatform enabling rapid clearance and effective tumor homing for oxygen-enhanced radiotherapy. Chem. Mater. 2018, 30, 5412–5421.
DOI Google Scholar
[23]

Liu, H. M.; Cheng, R.; Dong, X. H.; Zhu, S.; Zhou, R. Y.; Yan, L.; Zhang, C. Y.; Wang, Q.; Gu, Z. J.; Zhao, Y. L. BiO2−x nanosheets as radiosensitizers with catalase-like activity for hypoxia alleviation and enhancement of the radiotherapy of tumors. Inorg. Chem. 2020, 59, 3482–3493.
DOI Google Scholar
[24]

Liang, Y.; Peng, C.; Su, N.; Li, Q. Y.; Chen, S. W.; Wu, D.; Wu, B.; Gao, Y.; Xu, Z. T.; Dan, Q. et al. Tumor microenvironments self-activated cascade catalytic nanoscale metal organic frameworks as ferroptosis inducer for radiosensitization. Chem. Eng. J. 2022, 437, 135309.
DOI Google Scholar
[25]

Hu, H. L.; Zheng, S. T.; Hou, M. R.; Zhu, K.; Chen, C. Y.; Wu, Z. D.; Qi, L.; Ren, Y. Y.; Wu, B.; Xu, Y. K. et al. Functionalized Au@Cu-Sb-S nanoparticles for spectral CT/photoacoustic imaging-guided synergetic photo-radiotherapy in breast cancer. Int. J. Nanomed. 2022, 17, 395–407.
DOI Google Scholar
[26]

Pei, P.; Shen, W. H.; Zhang, Y.; Zhang, Y. X.; Qi, Z. Y.; Zhou, H. L.; Liu, T.; Sun, L.; Yang, K. Radioactive nano-oxygen generator enhance anti-tumor radio-immunotherapy by regulating tumor microenvironment and reducing proliferation. Biomaterials 2022, 280, 121326.
DOI Google Scholar
[27]

Meng, L. T.; Cheng, Y. L.; Tong, X. N.; Gan, S. J.; Ding, Y. W.; Zhang, Y.; Wang, C.; Xu, L.; Zhu, Y. S.; Wu, J. H. et al. Tumor oxygenation and hypoxia inducible factor-1 functional inhibition via a reactive oxygen species responsive nanoplatform for enhancing radiation therapy and abscopal effects. ACS Nano 2018, 12, 8308–8322.
DOI Google Scholar
[28]

Gong, N. Q.; Sheppard, N. C.; Billingsley, M. M.; June, C. H.; Mitchell, M. J. Nanomaterials for T-cell cancer immunotherapy. Nat. Nanotechnol. 2021, 16, 25–36.
DOI Google Scholar
[29]

Wang, J. P.; Sun, J. Y.; Hu, W.; Wang, Y. H.; Chou, T.; Zhang, B. L.; Zhang, Q.; Ren, L.; Wang, H. J. A porous Au@Rh bimetallic core–shell nanostructure as an H2O2-driven oxygenerator to alleviate tumor hypoxia for simultaneous bimodal imaging and enhanced photodynamic therapy. Adv. Mater. 2020, 32, 2001862.
DOI Google Scholar
[30]

Dan, Q.; Hu, D. H.; Ge, Y. S.; Zhang, S. Y.; Li, S. Q.; Gao, D. Y.; Luo, W. X.; Ma, T.; Liu, X.; Zheng, H. R. et al. Ultrasmall theranostic nanozymes to modulate tumor hypoxia for augmenting photodynamic therapy and radiotherapy. Biomater. Sci. 2020, 8, 973–987.
DOI Google Scholar
[31]

Lin, Y. H.; Ren, J. S.; Qu, X. G. Nano-gold as artificial enzymes: Hidden talents. Adv. Mater. 2014, 26, 4200–4217.
DOI Google Scholar
[32]

Long, Y. J.; Li, Y. F.; Liu, Y.; Zheng, J. J.; Tang, J.; Huang, C. Z. Visual observation of the mercury-stimulated peroxidase mimetic activity of gold nanoparticles. Chem. Commun. 2011, 47, 11939–11941.
DOI Google Scholar
[33]

Lien, C. W.; Huang, C. C.; Chang, H. T. Peroxidase-mimic bismuth-gold nanoparticles for determining the activity of thrombin and drug screening. Chem. Commun. 2012, 48, 7952–7954.
DOI Google Scholar
[34]

Bai, J.; Jia, X. D.; Ruan, Y. D.; Wang, C.; Jiang, X. E. Photosensitizer-conjugated Bi2Te3 nanosheets as theranostic agent for synergistic photothermal and photodynamic therapy. Inorg. Chem. 2018, 57, 10180–10188.
DOI Google Scholar
[35]

Hou, M. R.; Yan, C. G.; Chen, Z. L.; Zhao, Q. L.; Yuan, M. M.; Xu, Y. K.; Zhao, B. X. Multifunctional NIR-responsive poly(vinylpyrrolidone)-Cu-Sb-S nanotheranostic agent for photoacoustic imaging and photothermal/photodynamic therapy. Acta Biomater. 2018, 74, 334–343.
DOI Google Scholar
[36]

Xia, J.; Yao, J. J.; Wang, L. H. V. Photoacoustic tomography: Principles and advances (invited review). Prog. Electromagn. Res. 2014, 147, 1–22.
DOI Google Scholar
[37]

Gargiulo, S.; Albanese, S.; Mancini, M. State-of-the-art preclinical photoacoustic imaging in oncology: Recent advances in cancer theranostics. Contrast Media Mol. Imaging 2019, 2019, 1–24.
DOI Google Scholar
[38]

Wang, B.; Zhao, Q.; Zhang, Y. Y.; Liu, Z. J.; Zheng, Z. Z.; Liu, S. Y.; Meng, L. B.; Xin, Y.; Jiang, X. Targeting hypoxia in the tumor microenvironment: A potential strategy to improve cancer immunotherapy. J. Exp. Clin. Cancer Res. 2021, 40, 24.
DOI Google Scholar
[39]

Liu, X.; Ye, N. B.; Liu, S.; Guan, J. K.; Deng, Q. Y.; Zhang, Z. J.; Xiao, C.; Ding, Z. Y.; Zhang, B. X.; Chen, X. P. et al. Hyperbaric oxygen boosts PD-1 antibody delivery and T cell infiltration for augmented immune responses against solid tumors. Adv. Sci. 2021, 8, 2100233.
DOI Google Scholar
[40]

Hu, C.; He, X. Q.; Chen, Y. X.; Yang, X. T.; Qin, L.; Lei, T.; Zhou, Y.; Gong, T.; Huang, Y.; Gao, H. L. Metformin mediated PD-L1 downregulation in combination with photodynamic-immunotherapy for treatment of breast cancer. Adv. Funct. Mater. 2021, 31, 2007149.
DOI Google Scholar
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Publication history
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Acknowledgements

Publication history

Received: 15 March 2022
Revised: 07 June 2022
Accepted: 09 June 2022
Published: 05 August 2022
Issue date: January 2023

Copyright

© Tsinghua University Press 2022

Acknowledgements

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81871334, 81801764, 82072056, and 51937010), the Guangdong Basic and Applied Basic Research Foundation (Nos. 2017A050506011, 2018030310343, 2020B1515020008, 2021A1515012542, and 2021A1515011882), the Medical Scientific Research Foundation of Guangdong Province (No. A2018014), and the Pearl River Talented Young Scholar Program (No. 2017GC010282).

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