Skip to main content
SpringerLink
Log in

Nanozyme-Based Enhanced Cancer Immunotherapy

  • Review Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Catalytic nanoparticles with natural enzyme-mimicking properties, known as nanozymes, have emerged as excellent candidate materials for cancer immunotherapy. Owing to their enzymatic activities, artificial nanozymes not only serve as responsive carriers to load drugs and therapeutic molecules for cancer treatment, but also act as enzymes for modulating the immunosuppression of the tumor microenvironment (TME) via the catalytic activities of catalase, peroxidase, superoxide dismutase, and oxidase. The immunosuppressive pro-tumor TME can be reversed to the immunoactive anti-tumor TME by utilizing both reactive oxygen species (ROS)-generating and ROS-scavenging nanozymes, which enhance the efficacy of cancer immunotherapy. In this review, we introduce representative ROS-generating and ROS-scavenging nanozymes and discuss how artificial nanozymes respond to the conditions of the TME. Based on the mutual interaction between nanozymes and TME, recent therapeutic pathways to provoke anti-cancer immune responses using nanozymes are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Reproduced from [51] with permission from Wiley–VCH. Copyright 2021

Fig. 6

Reproduced from [52] with permission from Wiley–VCH. Copyright 2020

Fig. 7

Reproduced from [53] with permission from Elsevier. Copyright 2018

Fig. 8

Reproduced from [55] with permission from the American Chemical Society (ACS). Copyright 2020

Fig. 9

Reproduced from [61] with permission from Nature. Copyright 2017

Fig. 10

Reproduced from [63] with permission from Springer. Copyright 2019

Fig. 11

Reproduced from [62] with permission from Wiley–VCH. Copyright 2020

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA Cancer J Clin. 2021;71:7–33.

    Article  Google Scholar 

  2. Zhu G, Lynn GM, Jacobson O, Chen K, Liu Y, Zhang H, et al. Albumin/vaccine nanocomplexes that assemble in vivo for combination cancer immunotherapy. Nat Commun. 2017;8:1954.

    PubMed  PubMed Central  Google Scholar 

  3. Kuai R, Ochyl LJ, Bahjat KS, Schwendeman A, Moon JJ. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater. 2017;16:489–96.

    CAS  PubMed  Google Scholar 

  4. Kim J, Li WA, Choi Y, Lewin SA, Verbeke CS, Dranoff G, et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat Biotechnol. 2015;33:64–72.

    CAS  PubMed  Google Scholar 

  5. Sahin U, Türeci Ö. Personalized vaccines for cancer immunotherapy. Science. 2018;359:1355–60.

    CAS  PubMed  Google Scholar 

  6. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7:10501.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111:11774–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Topalian SL, Drake CG, Pardoll DM. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell. 2015;27:450–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhao J, Wen X, Tian L, Li T, Xu C, Wen X, et al. Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer. Nat Commun. 2019;10:899.

    PubMed  PubMed Central  Google Scholar 

  11. Chen Q, Hu Q, Dukhovlinova E, Chen G, Ahn S, Wang C, et al. Photothermal therapy promotes tumor infiltration and antitumor activity of CAR T cells. Adv Mater. 2019;31:e1900192.

    PubMed  PubMed Central  Google Scholar 

  12. Mohammed S, Sukumaran S, Bajgain P, Watanabe N, Heslop HE, Rooney CM, et al. Improving chimeric antigen receptor-modified T cell function by reversing the immunosuppressive tumor microenvironment of pancreatic cancer. Mol Ther. 2017;25:249–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Maus MV, June CH. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin Cancer Res. 2016;22:1875–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Brown CE, Alizadeh D, Starr R, Weng L, Wagner JR, Naranjo A, et al. Regression of Glioblastoma after chimeric antigen receptor T-cell therapy. N Engl J Med. 2016;375:2561–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Nguyen TL, Yin Y, Choi Y, Jeong JH, Kim J. Enhanced cancer DNA vaccine via direct transfection to host dendritic cells recruited in injectable scaffolds. ACS Nano. 2020;14:11623–36.

    CAS  PubMed  Google Scholar 

  16. Cha BG, Jeong JH, Kim J. Extra-large pore mesoporous silica nanoparticles enabling co-delivery of high amounts of protein antigen and toll-like receptor 9 agonist for enhanced cancer vaccine efficacy. ACS Cent Sci. 2018;4:484–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Nguyen TL, Cha BG, Choi Y, Im J, Kim J. Injectable dual-scale mesoporous silica cancer vaccine enabling efficient delivery of antigen/adjuvant-loaded nanoparticles to dendritic cells recruited in local macroporous scaffold. Biomaterials. 2020;239:119859.

    CAS  PubMed  Google Scholar 

  18. Lee JY, Kim MK, Nguyen TL, Kim J. Hollow mesoporous silica nanoparticles with extra-large mesopores for enhanced cancer vaccine. ACS Appl Mater Interfaces. 2020;12:34658–66.

    CAS  PubMed  Google Scholar 

  19. Kerr MD, McBride DA, Chumber AK, Shah NJ. Combining therapeutic vaccines with chemo- and immunotherapies in the treatment of cancer. Expert Opin Drug Discov. 2021;16:89–99.

    CAS  PubMed  Google Scholar 

  20. Guo C, Manjili MH, Subjeck JR, Sarkar D, Fisher PB, Wang XY. Chapter seven - therapeutic cancer vaccines: past, present, and future. In: Tew KD, Fisher PB, editors. Advances in Cancer Research. Cambridge: Academic Press; 2013. p. 421–75.

    Google Scholar 

  21. Farkona S, Diamandis EP, Blasutig IM. Cancer immunotherapy: the beginning of the end of cancer? BMC Med. 2016;14:73.

    PubMed  PubMed Central  Google Scholar 

  22. Duan X, Chan C, Lin W. Nanoparticle-mediated immunogenic cell death enables and potentiates cancer immunotherapy. Angew Chem Int Ed Engl. 2019;58:670–80.

    CAS  Google Scholar 

  23. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu Z, Ott PA, Wu CJ. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat Rev Immunol. 2018;18:168–82.

    CAS  PubMed  Google Scholar 

  26. Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11:509–24.

    CAS  PubMed  Google Scholar 

  27. Ma J, Qiu J, Wang S. Nanozymes for catalytic cancer immunotherapy. ACS Appl Nano Mater. 2020;3:4925–43.

    CAS  Google Scholar 

  28. Ying JF, Lu ZB, Fu LQ, Tong Y, Wang Z, Li WF, et al. The role of iron homeostasis and iron-mediated ROS in cancer. Am J Cancer Res. 2021;11:1895–912.

  29. Alizadeh D, Trad M, Hanke NT, Larmonier CB, Janikashvili N, Bonnotte B, et al. Doxorubicin eliminates myeloid-derived suppressor cells and enhances the efficacy of adoptive T-cell transfer in breast cancer. Can Res. 2014;74:104–18

    CAS  Google Scholar 

  30. Solito S, Marigo I, Pinton L, Damuzzo V, Mandruzzato S, Bronte V. Myeloid-derived suppressor cell heterogeneity in human cancers. Ann N Y Acad Sci. 2014;1319:47–65.

    CAS  PubMed  Google Scholar 

  31. Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW. Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother. 2011;60:1419–30.

  32. Meng X, Li D, Chen L, He H, Wang Q, Hong C, et al. High-performance self-cascade pyrite nanozymes for apoptosis-ferroptosis synergistic tumor therapy. ACS Nano. 2021;15:5735–51.

    CAS  PubMed  Google Scholar 

  33. Wang Q, Niu D, Shi J, Wang L. A three-in-one ZIFs-derived CuCo(O)/GOx@PCNs hybrid cascade nanozyme for immunotherapy/enhanced starvation/photothermal therapy. ACS Appl Mater Interfaces. 2021;13:11683–95.

    CAS  PubMed  Google Scholar 

  34. Zhou K, Cheng T, Zhan J, Peng X, Zhang Y, Wen J, et al. Targeting tumor-associated macrophages in the tumor microenvironment. Oncol Lett. 2020;20:234.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Pan Y, Yu Y, Wang X, Zhang T. Tumor-associated macrophages in tumor immunity. Front Immunol. 2020;11:583084.

    Google Scholar 

  36. Umansky V, Blattner C, Fleming V, Hu X, Gebhardt C, Altevogt P, et al. Myeloid-derived suppressor cells and tumor escape from immune surveillance. Semin Immunopathol. 2017;39:295–305.

    CAS  PubMed  Google Scholar 

  37. Wei T, Zhong W, Li Q. Role of heterogeneous regulatory T cells in the tumor microenvironment. Pharmacol Res. 2020;153:104659.

    PubMed  Google Scholar 

  38. Chaudhary B, Elkord E. Regulatory T cells in the tumor microenvironment and cancer progression: role and therapeutic targeting. Vaccines (Basel). 2016;4:28.

    PubMed Central  Google Scholar 

  39. Liu C, Workman CJ, Vignali DA. Targeting regulatory T cells in tumors. FEBS J. 2016;283:2731–48.

    CAS  PubMed  Google Scholar 

  40. Beyer M, Schultze LJ. Regulatory T cells: major players in the tumor microenvironment. Curr Pharm Des. 2009;15:1879–92.

    CAS  PubMed  Google Scholar 

  41. Zhang L, Wang S, Wang Y, Zhao W, Zhang Y, Zhang N, et al. Effects of hypoxia in intestinal tumors on immune cell behavior in the tumor microenvironment. Front Immunol. 2021;12:645320.

    Google Scholar 

  42. Li Y, Zhao L, Li XF. Hypoxia and the Tumor microenvironment. Technol Cancer Res Treat. 2021;20:15330338211036304.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Vito A, El-Sayes N, Mossman K. Hypoxia-driven immune escape in the tumor microenvironment. Cells. 2020;9:992.

    CAS  PubMed Central  Google Scholar 

  44. Bohme I, Bosserhoff AK. Acidic tumor microenvironment in human melanoma. Pigment Cell Melanoma Res. 2016;29:508–23.

    PubMed  Google Scholar 

  45. Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia–A2-adenosinergic tumor biology as the next Barrier to overcome for tumor immunologists. Cancer Immunol Res. 2014;2:598–605.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Barsoum IB, Smallwood CA, Siemens DR, Graham CH. A mechanism of hypoxia-mediated escape from adaptive immunity in cancer cells. Cancer Res. 2014;74:665–74.

    CAS  PubMed  Google Scholar 

  47. Aboelella NS, Brandle C, Kim T, Ding ZC, Zhou G. Oxidative stress in the tumor microenvironment and its relevance to cancer immunotherapy. Cancers. 2021;13:986.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang H, Cheng L, Ma S, Ding L, Zhang W, Xu Z, et al. Self-assembled multiple-enzyme composites for enhanced synergistic cancer starving-catalytic therapy. ACS Appl Mater Interfaces. 2020;12:20191–201.

    CAS  PubMed  Google Scholar 

  49. Chen M, Deng G, He Y, Li X, Liu W, Wang W, et al. Ultrasound-enhanced generation of reactive oxygen species for MRI-guided tumor therapy by the Fe@Fe3O4-based peroxidase-mimicking nanozyme. ACS Appl Bio Mater. 2019;3:639–47.

    Google Scholar 

  50. Lan M, Zhao S, Liu W, Lee CS, Zhang W, Wang P. Photosensitizers for photodynamic therapy. Adv Healthc Mater. 2019;8:e1900132.

    Google Scholar 

  51. Zhu L, Liu J, Zhou G, Liu TM, Dai Y, Nie G, et al. Remodeling of tumor microenvironment by tumor-targeting Nanozymes enhances immune activation of CAR T cells for combination therapy. Small. 2021;17:e2102624.

    PubMed  Google Scholar 

  52. Zhao Y, Xiao X, Zou M, Ding B, Xiao H, Wang M, et al. Nanozyme-initiated in situ cascade reactions for self-amplified biocatalytic immunotherapy. Adv Mater. 2021;33:e2006363.

    PubMed  Google Scholar 

  53. Liang R, Liu L, He H, Chen Z, Han Z, Luo Z, et al. Oxygen-boosted immunogenic photodynamic therapy with gold nanocages@manganese dioxide to inhibit tumor growth and metastases. Biomaterials. 2018;177:149–60.

    CAS  PubMed  Google Scholar 

  54. Gao L, Liu R, Gao F, Wang Y, Jiang X, Gao X. Plasmon-mediated generation of reactive oxygen species from near-infrared light excited gold nanocages for photodynamic therapy in vitro. ACS Nano. 2014;8:7260–71.

    CAS  PubMed  Google Scholar 

  55. Liu Y, Zhen W, Wang Y, Song S, Zhang H. Na2S2O8 nanoparticles trigger antitumor immunotherapy through reactive oxygen species storm and surge of tumor osmolarity. J Am Chem Soc. 2020;142:21751–7.

    CAS  PubMed  Google Scholar 

  56. Tang F, Du X, Liu M, Zheng P, Liu Y. Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade? Cell Biosci. 2018;8:30.

    PubMed  PubMed Central  Google Scholar 

  57. Chen H, Luan X, Paholak HJ, Burnett JP, Stevers NO, Sansanaphongpricha K, et al. Depleting tumor-associated Tregs via nanoparticle-mediated hyperthermia to enhance anti-CTLA-4 immunotherapy. Nanomedicine (Lond). 2019;15:77–92.

    PubMed Central  Google Scholar 

  58. Yao J, Cheng Y, Zhou M, Zhao S, Lin S, Wang X, et al. ROS scavenging Mn3O4 nanozymes for in vivo anti-inflammation. Chem Sci. 2018;9:2927–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kaizer J, Csay T, Kővári P, Speier G, Párkányi L. Catalase mimics of a manganese(II) complex: the effect of axial ligands and pH. J Mol Catal A Chem. 2008;280:203–9.

    CAS  Google Scholar 

  60. Singh N, Savanur MA, Srivastava S, D’Silva P, Mugesh G. A manganese oxide nanozyme prevents the oxidative damage of biomolecules without affecting the endogenous antioxidant system. Nanoscale. 2019;11:3855–63.

    CAS  PubMed  Google Scholar 

  61. Yang G, Xu L, Chao Y, Xu J, Sun X, Wu Y, et al. Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses. Nat Commun. 2017;8:902.

    PubMed  PubMed Central  Google Scholar 

  62. Xu B, Cui Y, Wang W, Li S, Lyu C, Wang S, et al. Immunomodulation-enhanced nanozyme-based tumor catalytic therapy. Adv Mater. 2020;32:e2003563.

    PubMed  Google Scholar 

  63. Wang J, Fang L, Li P, Ma L, Na W, Cheng C, et al. Inorganic nanozyme with combined self-oxygenation/degradable capabilities for sensitized cancer immunochemotherapy. Nanomicro Lett. 2019;11:74.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by grant from the National Research Foundation (NRF) of Korea (No. 2020M3A9D3039720) funded by the Korean government (MSIT) and the R&D Program for Forest Science Technology (No. 2020209B10-2222-BA01) provided by the Korea Forest Service (KFS) of the Korea Forestry Promotion Institute. Ngoc Man Phan and Thanh Loc Nguyen contributed equally to this work. All authors approved the final version of the manuscript. Correspondence should be addressed to Jaeyun Kim.

Author information

Authors and Affiliations

  1. School of Chemical Engineering, Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea

    Ngoc Man Phan, Thanh Loc Nguyen & Jaeyun Kim

  2. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea

    Jaeyun Kim

  3. Biomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University (SKKU), Suwon, 16419, Republic of Korea

    Jaeyun Kim

  4. Institute of Quantum Biophysics (IQB), Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Jaeyun Kim

Authors
  1. Ngoc Man Phan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thanh Loc Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jaeyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jaeyun Kim.

Ethics declarations

Conflicts of interest

The authors declare no competing financial interest.

Ethical Statement

There are no animal experiments carried out for this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Phan, N.M., Nguyen, T.L. & Kim, J. Nanozyme-Based Enhanced Cancer Immunotherapy. Tissue Eng Regen Med 19, 237–252 (2022). https://doi.org/10.1007/s13770-022-00430-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-022-00430-y

Keywords

Search

Navigation