Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies

An Author Correction to this article was published on 15 April 2025

This article has been updated

Abstract

The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8+ T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Development of SynVACs to mimic the viscoelastic properties of native APCs using a microfluidic device.
Fig. 2: Characterization of SynVACs in terms of stiffness, viscoelasticity and ligand density.
Fig. 3: Polyclonal expansion of primary human T cells by SynVACs results in a higher TMSC population.
Fig. 4: SynVACs enhance the transduction efficiency and tumour-killing capacity of CAR T cells.
Fig. 5: scRNAseq analysis reveals distinct activation patterns and gene expression profiles in CAR T cells activated by SynVACs and Dynabeads.
Fig. 6: In vivo efficacy of SynVAC-activated CAR19 T cells in a human lymphoma Raji xenograft mouse model.
Fig. 7: In vivo efficacy of SynVAC-activated MCAR T cells in a human ovarian solid tumour xenograft mouse model.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data for the figures, are available via figshare at https://doi.org/10.6084/m9.figshare.25928314 (ref. 67). Source data are provided with this paper.

Code availability

scRNAseq data generated from this study, the processed cell matrix, data tables (such as expression values) and metadata are available from the Gene Expression Omnibus database via the accession code GSE242531.

Change history

References

  1. Safarzadeh Kozani, P., Safarzadeh Kozani, P. & Rahbarizadeh, F. CAR-T cell therapy in T-cell malignancies: is success a low-hanging fruit? Stem Cell Res. Ther. 12, 527 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Zhang, Z. Z. et al. Improving the ability of CAR-T cells to hit solid tumors: challenges and strategies. Pharmacol. Res. 175, 106036 (2022).

    Article  CAS  PubMed  Google Scholar 

  4. Yan, T., Zhu, L. & Chen, J. Current advances and challenges in CAR T-cell therapy for solid tumors: tumor-associated antigens and the tumor microenvironment. Exp. Hematol. Oncol. 12, 14 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Li, Y. R., Dunn, Z. S., Zhou, Y., Lee, D. & Yang, L. Development of stem cell-derived immune cells for off-the-shelf cancer immunotherapies. Cells 10, 3497 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jiang, Y., Li, Y. & Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dolina, J. S., Van Braeckel-Budimir, N., Thomas, G. D. & Salek-Ardakani, S. CD8(+) T cell exhaustion in cancer. Front. Immunol. 12, 715234 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li, Y. R. et al. Advancing cell-based cancer immunotherapy through stem cell engineering. Cell Stem Cell 30, 592–610 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gattinoni, L., Speiser, D. E., Lichterfeld, M. & Bonini, C. T memory stem cells in health and disease. Nat. Med. 23, 18–27 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Blaeschke, F. et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4(+) and CD8(+) CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19(+) acute lymphoblastic leukemia. Cancer Immunol. Immunother. 67, 1053–1066 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gattinoni, L., Klebanoff, C. A. & Restifo, N. P. Paths to stemness: building the ultimate antitumour T cell. Nat. Rev. Cancer 12, 671–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xu, L. et al. Memory T cells skew toward terminal differentiation in the CD8+ T cell population in patients with acute myeloid leukemia. J. Hematol. Oncol. 11, 93 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Scholz, G. et al. Modulation of mTOR signalling triggers the formation of stem cell-like memory T cells. EBioMedicine 4, 50–61 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Fowler, D. H. & Gattinoni, L. T memory stem cell formation: caveat mTOR. EBioMedicine 4, 3–4 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Eggermont, L. J., Paulis, L. E., Tel, J. & Figdor, C. G. Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells. Trends Biotechnol. 32, 456–465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Oh, J. et al. The effect of the nanoparticle shape on T cell activation. Small 18, e2107373 (2022).

    Article  PubMed  Google Scholar 

  18. Majedi, F. S. et al. Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells. Nano Lett. 19, 6945–6954 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Majedi, F. S. et al. Systemic enhancement of antitumour immunity by peritumourally implanted immunomodulatory macroporous scaffolds. Nat. Biomed. Eng. 7, 56–71 (2023).

    Article  CAS  PubMed  Google Scholar 

  20. Mossman, K. D., Campi, G., Groves, J. T. & Dustin, M. L. Altered TCR signaling from geometrically repatterned immunological synapses. Science 310, 1191–1193 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. O’Connor, R. S. et al. Substrate rigidity regulates human T cell activation and proliferation. J. Immunol. 189, 1330–1339 (2012).

    Article  PubMed  Google Scholar 

  22. Kim, H. S. et al. Dendritic cell-mimicking scaffolds for ex vivo T cell expansion. Bioact. Mater. 21, 241–252 (2023).

    CAS  PubMed  Google Scholar 

  23. Chen, B. et al. Janus particles as artificial antigen-presenting cells for T cell activation. ACS Appl. Mater. Interfaces 6, 18435–18439 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Agarwalla, P. et al. Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells. Nat. Biotechnol. 40, 1250–1258 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Vormittag, P., Gunn, R., Ghorashian, S. & Veraitch, F. S. A guide to manufacturing CAR T cell therapies. Curr. Opin. Biotechnol. 53, 164–181 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Delcassian, D., Sattler, S. & Dunlop, I. E. T cell immunoengineering with advanced biomaterials. Integr. Biol. 9, 211–222 (2017).

    Article  CAS  Google Scholar 

  27. Saruwatari, L. et al. Osteoblasts generate harder, stiffer, and more delamination-resistant mineralized tissue on titanium than on polystyrene, associated with distinct tissue micro- and ultrastructure. J. Bone Miner. Res. 20, 2002–2016 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Chaudhuri, O., Cooper-White, J., Janmey, P. A., Mooney, D. J. & Shenoy, V. B. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Saitakis, M. et al. Different TCR-induced T lymphocyte responses are potentiated by stiffness with variable sensitivity. Elife 6, e23190 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhang, X. et al. Unraveling the mechanobiology of immune cells. Curr. Opin. Biotechnol. 66, 236–245 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ma, Y. et al. Viscoelastic cell microenvironment: hydrogel-based strategy for recapitulating dynamic ECM mechanics. Adv. Funct. Mater. 31, 2100848 (2021).

    Article  CAS  Google Scholar 

  32. Wu, D. T., Jeffreys, N., Diba, M. & Mooney, D. J. Viscoelastic biomaterials for tissue regeneration. Tissue Eng. C 28.7, 289–300 (2022).

    Article  Google Scholar 

  33. Huebsch, N. Translational mechanobiology: designing synthetic hydrogel matrices for improved in vitro models and cell-based therapies. Acta Biomater. 94, 97–111 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Liu, Z. et al. Three-dimensional hepatic lobule-like tissue constructs using cell-microcapsule technology. Acta Biomater. 50, 178–187 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Liu, Z. et al. Shape-controlled high cell-density microcapsules by electrodeposition. Acta Biomater. 37, 93–100 (2016).

    Article  PubMed  Google Scholar 

  36. Donati, I. & Paoletti, S. in Alginates: Biology and Applications (ed. Rehm, B. H. A.) 1–53 (Springer, 2009).

  37. Liu, Z. et al. Selective formation of osteogenic and vasculogenic tissues for cartilage regeneration. Adv. Healthc. Mater. 12, 2202008 (2023).

    Article  CAS  Google Scholar 

  38. Tanaka, H., Matsumura, M. & Veliky, I. A. Diffusion characteristics of substrates in Ca-alginate gel beads. Biotechnol. Bioeng. 26, 53–58 (1984).

    Article  CAS  PubMed  Google Scholar 

  39. Martinsen, A., Skjak-Braek, G. & Smidsrod, O. Alginate as immobilization material: I. Correlation between chemical and physical properties of alginate gel beads. Biotechnol. Bioeng. 33, 79–89 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Fan, Y. et al. Alginate enhances memory properties of antitumor CD8+ T cells by promoting cellular antioxidation. ACS Biomater. Sci. Eng. 5, 4717–4725 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Shaebani, M. R. et al. Effects of vimentin on the migration, search efficiency, and mechanical resilience of dendritic cells. Biophys. J. 18, 3950–3961 (2022).

    Article  Google Scholar 

  42. Maggi, A. et al. Development of a novel antibody–tetrazine conjugate for bioorthogonal pretargeting. Org. Biomol. Chem. 14, 7544–7551 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Cai, H. et al. Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering. Nat. Nanotechnol. 13, 610–617 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hernandez-Lopez, R. A. et al. T cell circuits that sense antigen density with an ultrasensitive threshold. Science 371, 1166–1171 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Deeg, J. et al. T cell activation is determined by the number of presented antigens. Nano Lett. 13, 5619–5626 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hickey, J. W. et al. Engineering an artificial T-cell stimulating matrix for immunotherapy. Adv. Mater. 31, e1807359 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Cheung, A. S., Zhang, D. K. Y., Koshy, S. T. & Mooney, D. J. Scaffolds that mimic antigen-presenting cells enable ex vivo expansion of primary T cells. Nat. Biotechnol. 36, 160–169 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, D. K. Y. et al. Enhancing CAR-T cell functionality in a patient-specific manner. Nat. Commun. 14, 506 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Durgeau, A., Virk, Y., Corgnac, S. & Mami-Chouaib, F. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front. Immunol. 9, 14 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wang, Z. et al. Isolation of tumour-reactive lymphocytes from peripheral blood via microfluidic immunomagnetic cell sorting. Nat. Biomed. Eng. 7, 1188–1203 (2023).

    Article  CAS  PubMed  Google Scholar 

  51. Bai, Z. et al. Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL. Sci. Adv. 8, eabj2820 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Clarke, S. L. et al. CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer. PLoS ONE 1, e129 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Guo, B. et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J. Cell. Immunother. 2, 28–35 (2016).

    Article  Google Scholar 

  54. Wang, Z. et al. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell. Mol. Immunol. 18, 2188–2198 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Levine, B. L., Miskin, J., Wonnacott, K. & Keir, C. Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92–101 (2017).

    Article  CAS  PubMed  Google Scholar 

  56. Adu-Berchie, K. et al. Generation of functionally distinct T-cell populations by altering the viscoelasticity of their extracellular matrix. Nat. Biomed. Eng 7, 1374–1391 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Henning, A. N., Roychoudhuri, R. & Restifo, N. P. Epigenetic control of CD8(+) T cell differentiation. Nat. Rev. Immunol. 18, 340–356 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lei, K. et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat. Biomed. Eng. 5, 1411–1425 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhang, J. et al. Osr2 functions as a biomechanical checkpoint to aggravate CD8(+) T cell exhaustion in tumor. Cell 187, 3409–3426 (2024).

    Article  CAS  PubMed  Google Scholar 

  60. Utech, S. et al. Microfluidic generation of monodisperse, structurally homogeneous alginate microgels for cell encapsulation and 3D cell culture. Adv. Health. Mater. 4, 1628–1633 (2015).

    Article  CAS  Google Scholar 

  61. Zeyang, L. et al. Mild formation of core-shell hydrogel microcapsules for cell encapsulation. Biofabrication 13, 025002 (2020).

    Google Scholar 

  62. Delcassian, D. et al. Nanoscale ligand spacing influences receptor triggering in T cells and NK cells. Nano Lett. 13, 5608–5614 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Grindy, S. C. et al. Control of hierarchical polymer mechanics with bioinspired metal-coordination dynamics. Nat. Mater. 14, 1210–1216 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rotsch, C., Jacobson, K. & Radmacher, M. Dimensional and mechanical dynamics of active and stable edges in motile fibroblasts investigated by using atomic force microscopy. Proc. Natl Acad. Sci. USA 96, 921–926 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li, Y. R. et al. Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy. Cell Rep. Med. 2, 100449 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Zhu, Y. et al. Development of hematopoietic stem cell-engineered invariant natural killer T cell therapy for cancer. Cell Stem Cell 25, 542–557 e549 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Liu, Z. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. figshare https://doi.org/10.6084/m9.figshare.25928314 (2024).

Download references

Acknowledgements

This work was supported in part by a UCLA Jonsson Comprehensive Cancer Center (JCCC) Seed Grant (to S.L. and L.Y.), a UCLA Broad Stem Cell Research Center (BSCRC) Innovation Award (to S.L.), a grant from the National Institutes of Health (NIH) (GM143485, to S.L.), a Discovery Stage Award from the California Institute for Regenerative Medicine (CIRM) (DISC2-14169, to S.L.) and an Ablon Scholars Award (to L.Y.). Y.-R.L. is a postdoctoral fellow supported by a UCLA Microbiology, Immunology, and Molecular Genetics M. John Pickett Post-Doctoral Fellow Award and a CIRM-BSCRC Postdoctoral Fellowship. E.Z. acknowledges the NIH/National Heart, Lung, and Blood Institute (NHLBI) T32HL144449. E.Z. and T.H. acknowledge the NIH/NHLBI R01HL129727 and NIH/NHLBI R01HL159970. We thank the UCLA Division of Laboratory Animal Medicine (DLAM) for providing animal support, the UCLA BSCRC Flow Cytometry Core Facility for providing cell sorting support, the UCLA TCGB facility for providing scRNAseq services, the UCLA Center for AIDS Research (CFAR) Virology Core for providing human PBMCs and the Advanced Light Microscopy/Spectroscopy Laboratory and the Leica Microsystems Center at the California NanoSystems Institute for supporting the image acquisition. We also thank the NIH Tetramer Facility for providing the tetramers, and the Christopher Seet Lab (UCLA) for providing the human Jurkat T-cell line and Jurkat NFAT-zsGreen reporter cell line used in this study.

Author information

Authors and Affiliations

Authors

Contributions

Z. Liu, Y.-R.L., L.Y. and S.L. designed the experiments. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., M.M.H.-S., E.Z., H.N., J.Z., X.G., Z. Li, K.-W.Y., Yichen Zhu and Y.F. performed the experiments. Z. Liu, Y.-R.L., Yu Zhu, E.Z., J. Shen and Y.Y. analysed the data. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., E.Z., Y.W., T.H., W.Y., J. Soto, T.H., L.Y. and S.L. discussed and interpreted the results. Z. Liu, Y.-R.L., Yu Zhu, Y.Y., E.Z., L.Y. and S.L. wrote and revised the manuscript.

Corresponding authors

Correspondence to Lili Yang or Song Li.

Ethics declarations

Competing interests

Z. Liu, Y.-R.L., L.Y. and S.L. filed a patent application (PCT/US24/22516) on SynVAC as inventors. The other authors declare no competing interests.

Peer review

Peer review information

Nature Biomedical Engineering thanks Paolo Provenzano and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Additional information

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

Supplementary information

Supplementary Information

Supplementary Figures and Tables.

Reporting Summary

Peer Review File

Supplementary Video 1

Microsphere fabrication.

Supplementary Video 2

Co-culture of SynVACs.

Supplementary Video 3

Co-culture of Dynabeads.

Source data

Source Data Fig. 6

Source data for tumour burden.

Source Data Fig. 7

Source data for tumour burden.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, Z., Li, YR., Yang, Y. et al. Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies. Nat. Biomed. Eng 8, 1615–1633 (2024). https://doi.org/10.1038/s41551-024-01272-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41551-024-01272-w

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer