Biomaterial-assisted targeted modulation of immune cells in cancer treatment


The past decade has witnessed the accelerating development of immunotherapies for cancer treatment. Immune checkpoint blockade therapies and chimeric antigen receptor (CAR)-T cell therapies have demonstrated clinical efficacy against a variety of cancers. However, issues including life-threatening off-target side effects, long processing times, limited patient responses and high cost still limit the clinical utility of cancer immunotherapies. Biomaterial carriers of these therapies, though, enable one to troubleshoot the delivery issues, amplify immunomodulatory effects, integrate the synergistic effect of different molecules and, more importantly, home and manipulate immune cells in vivo. In this Review, we will analyse thus-far developed immunomaterials for targeted modulation of dendritic cells, T cells, tumour-associated macrophages, myeloid-derived suppressor cells, B cells and natural killer cells, and summarize the promises and challenges of cell-targeted immunomodulation for cancer treatment.

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Fig. 1: Overview of targets of cancer immunotherapies.
Fig. 2: Nanomaterial vaccines for modulation of DCs.
Fig. 3: Biomaterial scaffold-based cancer vaccines.
Fig. 4: Materials for ex vivo expansion of T cells.
Fig. 5: Materials for checkpoint blockade therapies.
Fig. 6: Materials for modulation of tumour-associated macrophages (TAMs).


  1. 1.

    Stewart, B. & Wild, C. P. World Cancer Report 2014 (World Health Organization, 2017).

  2. 2.

    Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat. Rev. Clin. Oncol. 13, 273–290 (2016).

    Article  CAS  Google Scholar 

  3. 3.

    Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).

    Article  CAS  Google Scholar 

  4. 4.

    Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  Google Scholar 

  5. 5.

    Melero, I. et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat. Rev. Clin. Oncol. 11, 509–524 (2014).

    Article  CAS  Google Scholar 

  6. 6.

    Teng, F., Meng, X., Kong, L. & Yu, J. Progress and challenges of predictive biomarkers of anti PD-1/PD-L1 immunotherapy: A systematic review. Cancer lett. 414, 166–173 (2018).

    Article  CAS  Google Scholar 

  7. 7.

    Srivastava, S. & Riddell, S. R. Chimeric antigen receptor T cell therapy: challenges to bench-to-bedside efficacy. J. Immunol. 200, 459–468 (2018).

    Article  CAS  Google Scholar 

  8. 8.

    Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    Article  CAS  Google Scholar 

  9. 9.

    Weber, J. S. & Mulé, J. J. Cancer immunotherapy meets biomaterials. Nat. Biotechnol. 33, 44–45 (2015).

    Article  CAS  Google Scholar 

  10. 10.

    Fan, Y. & Moon, J. J. Nanoparticle drug delivery systems designed to improve cancer vaccines and immunotherapy. Vaccines 3, 662–685 (2015).

    Article  CAS  Google Scholar 

  11. 11.

    Irvine, D. J., Hanson, M. C., Rakhra, K. & Tokatlian, T. Synthetic nanoparticles for vaccines and immunotherapy. Chem. Rev. 115, 11109–11146 (2015).

    Article  CAS  Google Scholar 

  12. 12.

    Koshy, S. T. & Mooney, D. J. Biomaterials for enhancing anti-cancer immunity. Curr. Opin. Biotechnol. 40, 1–8 (2016).

    Article  CAS  Google Scholar 

  13. 13.

    Wang, C., Ye, Y., Hochu, G. M., Sadeghifar, H. & Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett. 16, 2334–2340 (2016).

    Article  CAS  Google Scholar 

  14. 14.

    Chen, Q. et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun. 7, 13193 (2016).

    Article  CAS  Google Scholar 

  15. 15.

    Stephan, M. T., Moon, J. J., Um, S. H., Bershteyn, A. & Irvine, D. J. Therapeutic cell engineering with surface-conjugated synthetic nanoparticles. Nat. Med. 16, 1035–1041 (2010).

    Article  CAS  Google Scholar 

  16. 16.

    Moyer, T. J., Zmolek, A. C. & Irvine, D. J. Beyond antigens and adjuvants: formulating future vaccines. J. Clin. Investig. 126, 799–808 (2016).

    Article  Google Scholar 

  17. 17.

    Milling, L., Zhang, Y. & Irvine, D. J. Delivering safer immunotherapies for cancer. Adv. Drug Deliv. Rev. 114, 79–101 (2017).

    Article  CAS  Google Scholar 

  18. 18.

    Paavonen, J. et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374, 301–314 (2009).

    Article  CAS  Google Scholar 

  19. 19.

    Wiemann, B. & Starnes, C. O. Coley’s toxins, tumour necrosis factor and cancer research: a historical perspective. Pharmacol. Ther. 64, 529–564 (1994).

    Article  CAS  Google Scholar 

  20. 20.

    Dranoff, G. et al. Vaccination with irradiated tumour cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting antitumour immunity. Proc. Natl Acad. Sci. USA 90, 3539–3543 (1993).

    Article  CAS  Google Scholar 

  21. 21.

    Mach, N. & Dranoff, G. Cytokine-secreting tumour cell vaccines. Curr. Opin. Immunol. 12, 571–575 (2000).

    Article  CAS  Google Scholar 

  22. 22.

    Copier, J. & Dalgleish, A. Overview of tumour cell–based vaccines. Int. Rev. Immunol. 25, 297–319 (2006).

    Article  CAS  Google Scholar 

  23. 23.

    Kantoff, P. W. et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363, 411–422 (2010).

    Article  CAS  Google Scholar 

  24. 24.

    Cheever, M. A. & Higano, C. S. PROVENGE (sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin. Cancer Res. 17, 3520–3526 (2011).

    Article  Google Scholar 

  25. 25.

    Muraoka, D. et al. Nanogel-based immunologically stealth vaccine targets macrophages in the medulla of lymph node and induces potent antitumour immunity. ACS Nano 8, 9209–9218 (2014).

    Article  CAS  Google Scholar 

  26. 26.

    Moon, J. J. et al. Interbilayer-crosslinked multilamellar vesicles as synthetic vaccines for potent humoral and cellular immune responses. Nat. Mater. 10, 243–251 (2011).

    Article  CAS  Google Scholar 

  27. 27.

    Kuai, R., Ochyl, L. J., Bahjat, K. S., Schwendeman, A. & Moon, J. J. Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat. Mater. 16, 489–496 (2017).

    Article  CAS  Google Scholar 

  28. 28.

    Lynn, G. M. et al. In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity. Nat. Biotechnol. 33, 1201–1210 (2015).

    Article  CAS  Google Scholar 

  29. 29.

    Benne, N., van Duijn, J., Kuiper, J., Jiskoot, W. & Slütter, B. Orchestrating immune responses: How size, shape and rigidity affect the immunogenicity of particulate vaccines. J. Control. Release 234, 124–134 (2016).

    Article  CAS  Google Scholar 

  30. 30.

    Walkey, C. D., Olsen, J. B., Guo, H., Emili, A. & Chan, W. C. Nanoparticle size and surface chemistry determine serum protein adsorption and macrophage uptake. J. Am. Chem. Soc. 134, 2139–2147 (2012).

    Article  CAS  Google Scholar 

  31. 31.

    Kasturi, S. P. et al. Programming the magnitude and persistence of antibody responses with innate immunity. Nature 470, 543–547 (2011).

    Article  CAS  Google Scholar 

  32. 32.

    Mohsen, M. O. et al. Delivering adjuvants and antigens in separate nanoparticles eliminates the need of physical linkage for effective vaccination. J. Control. Release 251, 92–100 (2017).

    Article  CAS  Google Scholar 

  33. 33.

    Flach, T. L. et al. Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat. Med. 17, 479–487 (2011).

    Article  CAS  Google Scholar 

  34. 34.

    Ng, G. et al. Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and syk kinase activation in dendritic cells. Immunity 29, 807–818 (2008).

    Article  CAS  Google Scholar 

  35. 35.

    Luo, M. et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotech. 12, 648–654 (2017).

    Article  CAS  Google Scholar 

  36. 36.

    Oussoren, C., Zuidema, J., Crommelin, D. J. A. & Storm, G. Lymphatic uptake and biodistribution of liposomes after subcutaneous injection: II. Influence of liposomal size, lipid composition and lipid dose. Biochim. Biophys. Acta 1328, 261–272 (1997).

    Article  CAS  Google Scholar 

  37. 37.

    Reddy, S. T., Rehor, A., Schmoekel, H. G., Hubbell, J. A. & Swartz, M. A. In vivo targeting of dendritic cells in lymph nodes with poly (propylene sulfide) nanoparticles. J. Control. Release 112, 26–34 (2006).

    Article  CAS  Google Scholar 

  38. 38.

    Mueller, S. N., Tian, S. & DeSimone, J. M. Rapid and persistent delivery of antigen by lymph node targeting PRINT nanoparticle vaccine carrier to promote humoral immunity. Mol. Pharm. 12, 1356–1365 (2015).

    Article  CAS  Google Scholar 

  39. 39.

    Caminschi, I., Maraskovsky, E. & Heath, W. R. Targeting dendritic cells in vivo for cancer therapy. Front. Immunol. (2012).

  40. 40.

    Rosalia, R. A. et al. CD40-targeted dendritic cell delivery of PLGA-nanoparticle vaccines induce potent antitumour responses. Biomaterials 40, 88–97 (2015).

    Article  CAS  Google Scholar 

  41. 41.

    Chen, P. et al. Dendritic cell targeted vaccines: Recent progresses and challenges. Hum. Vaccines Immunother. 12, 612–622 (2016).

    Article  Google Scholar 

  42. 42.

    Liu, H. et al. Structure-based programming of lymph-node targeting in molecular vaccines. Nature 507, 519–522 (2014).

    Article  CAS  Google Scholar 

  43. 43.

    Jabulowsky, R. A. et al. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent melanoma immunotherapy. Cancer Res. 77, CT034 (2017).

    Article  Google Scholar 

  44. 44.

    Study of DPX-Survivac vaccine therapy and epacadostat in patients with recurrent ovarian cancer. (2017).

  45. 45.

    Berinstein, N. L. et al. Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients. Oncoimmunology 4, e1026529 (2015).

    Article  CAS  Google Scholar 

  46. 46.

    Berinstein, N. L. et al. First-in-man application of a novel therapeutic cancer vaccine formulation with the capacity to induce multi-functional T cell responses in ovarian, breast and prostate cancer patients. J. Transl. Med. 10, 156–156 (2012).

    Article  CAS  Google Scholar 

  47. 47.

    Karkada, M., Berinstein, N. L. & Mansour, M. Therapeutic vaccines and cancer: focus on DPX-0907. Biol. Targets Ther. 8, 27–38 (2014).

    Article  CAS  Google Scholar 

  48. 48.

    Safety study of a recombinant protein vaccine to treat esophageal cancer. (2013).

  49. 49.

    Kageyama, S. et al. Dose-dependent effects of NY-ESO-1 protein vaccine complexed with cholesteryl pullulan (CHP-NY-ESO-1) on immune responses and survival benefits of esophageal cancer patients. J. Transl. Med. 11, 246–246 (2013).

    Article  CAS  Google Scholar 

  50. 50.

    Gribben, J. G. et al. Unexpected association between induction of immunity to the universal tumour antigen CYP1B1 and response to next therapy. Clin. Cancer Res. 11, 4430–4436 (2005).

    Article  CAS  Google Scholar 

  51. 51.

    Pitt, J. M. et al. Dendritic cell–derived exosomes for cancer therapy. J. Clin. Investig. 126, 1224–1232 (2016).

    Article  Google Scholar 

  52. 52.

    Li, Y. et al. Tumor-derived autophagosome vaccine: mechanism of cross-presentation and therapeutic efficacy. Clin. Cancer Res. 17, 7047–7057 (2011).

    Article  CAS  Google Scholar 

  53. 53.

    Combination vaccine immunotherapy (dribbles) for patients with definitively-treated stage III non-small cell lung cancer. (2017).

  54. 54.

    Ali, O. A., Huebsch, N., Cao, L., Dranoff, G. & Mooney, D. J. Infection-mimicking materials to program dendritic cells in situ. Nat. Mater. 8, 151–158 (2009).

    Article  CAS  Google Scholar 

  55. 55.

    Ali, O. A., Emerich, D., Dranoff, G. & Mooney, D. J. In situ regulation of DC subsets and T cells mediates tumour regression in mice. Sci. Transl. Med. 1, 8ra19 (2009).

    Article  CAS  Google Scholar 

  56. 56.

    Ali, O. A. et al. Biomaterial-Based Vaccine Induces Regression of Established Intracranial Glioma in Rats. Pharm. Res. 28, 1074–1080 (2011).

    Article  CAS  Google Scholar 

  57. 57.

    Dendritic cell activating scaffold in melanoma. (2017).

  58. 58.

    Kim, J. et al. Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy. Nat. Biotechnol. 33, 64–72 (2015).

    Article  CAS  Google Scholar 

  59. 59.

    Li, A. W. et al. A facile approach to enhance antigen response for personalized cancer vaccination. Nat. Mater. (2018).

  60. 60.

    Singh, A., Suri, S. & Roy, K. In-situ crosslinking hydrogels for combinatorial delivery of chemokines and siRNA–DNA carrying microparticles to dendritic cells. Biomaterials 30, 5187–5200 (2009).

    Article  CAS  Google Scholar 

  61. 61.

    DeMuth, P. C. et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nat. Mater. 12, 367–376 (2013).

    Article  CAS  Google Scholar 

  62. 62.

    Verbeke, C. S. & Mooney, D. J. Injectable, pore-forming hydrogels for in vivo enrichment of immature dendritic cells. Adv. Healthc. Mater. 4, 2677–2687 (2015).

    Article  CAS  Google Scholar 

  63. 63.

    Verbeke, C. S. et al. Multicomponent injectable hydrogels for antigen-specific tolerogenic immune modulation. Adv. Healthc. Mater. 6, 1600773 (2017).

    Article  CAS  Google Scholar 

  64. 64.

    Bencherif, S. A. et al. Injectable cryogel-based whole-cell cancer vaccines. Nat. Commun. 6, 7556 (2015).

    Article  CAS  Google Scholar 

  65. 65.

    Sexton, A. et al. A protective vaccine delivery system for in vivo T cell stimulation using nanoengineered polymer hydrogel capsules. ACS Nano 3, 3391–3400 (2009).

    Article  CAS  Google Scholar 

  66. 66.

    Umeki, Y. et al. Induction of potent antitumour immunity by sustained release of cationic antigen from a DNA‐based hydrogel with adjuvant activity. Adv. Funct. Mater. 25, 5758–5767 (2015).

    Article  CAS  Google Scholar 

  67. 67.

    Nishikawa, M. et al. Injectable, self-gelling, biodegradable, and immunomodulatory DNA hydrogel for antigen delivery. J. Control. Release 180, 25–32 (2014).

    Article  CAS  Google Scholar 

  68. 68.

    Park, C. G. et al. Extended release of perioperative immunotherapy prevents tumour recurrence and eliminates metastases. Sci. Transl. Med. 10, eaar1916 (2018).

    Article  Google Scholar 

  69. 69.

    Kim, Y.-C., Park, J.-H. & Prausnitz, M. R. Microneedles for drug and vaccine delivery. Adv. Drug Deliv. Rev. 64, 1547–1568 (2012).

    Article  CAS  Google Scholar 

  70. 70.

    DeMuth, P. C. et al. Polymer multilayer tattooing for enhanced DNA vaccination. Nat. Mater. 12, 367–376 (2013).

    Article  CAS  Google Scholar 

  71. 71.

    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  Google Scholar 

  72. 72.

    Zheng, Y. et al. In vivo targeting of adoptively transferred T-cells with antibody- and cytokine-conjugated liposomes. J. Control. Release 172, 426–435 (2013).

    Article  CAS  Google Scholar 

  73. 73.

    Francis, D. M. & Thomas, S. N. Progress and opportunities for enhancing the delivery and efficacy of checkpoint inhibitors for cancer immunotherapy. Adv. Drug Deliv. Rev. 15, 33–42 (2017).

    Article  CAS  Google Scholar 

  74. 74.

    Meir, R. et al. Fast image-guided stratification using anti-programmed death ligand 1 gold nanoparticles for cancer immunotherapy. ACS Nano 11, 11127–11134 (2017).

    Article  CAS  Google Scholar 

  75. 75.

    Sunshine, J. C., Perica, K., Schneck, J. P. & Green, J. J. Particle shape dependence of CD8+ T cell activation by artificial antigen presenting cells. Biomaterials 35, 269–277 (2014).

    Article  CAS  Google Scholar 

  76. 76.

    Steenblock, E. R. & Fahmy, T. M. A comprehensive platform for ex vivo T-cell expansion based on biodegradable polymeric artificial antigen-presenting cells. Mol. Ther. 16, 765–772 (2008).

    Article  CAS  Google Scholar 

  77. 77.

    Prakken, B. et al. Artificial antigen-presenting cells as a tool to exploit the immune ‘synapse’. Nat. Med. 6, 1406–1410 (2000).

    Article  CAS  Google Scholar 

  78. 78.

    Perica, K. et al. Magnetic field-induced T cell receptor clustering by nanoparticles enhances T cell activation and stimulates antitumour activity. ACS Nano 8, 2252–2260 (2014).

    Article  CAS  Google Scholar 

  79. 79.

    Fadel, T. R. et al. A carbon nanotube–polymer composite for T-cell therapy. Nat. Nanotech. 9, 639–647 (2014).

    Article  CAS  Google Scholar 

  80. 80.

    Rasmussen, A.-M. et al. Ex vivo expansion protocol for human tumour specific T cells for adoptive T cell therapy. J. Immunol. Methods 355, 52–60 (2010).

    Article  CAS  Google Scholar 

  81. 81.

    Gijs, M. A. M., Lacharme, F. & Lehmann, U. Microfluidic applications of magnetic particles for biological analysis and catalysis. Chem. Rev. 110, 1518–1563 (2010).

    Article  CAS  Google Scholar 

  82. 82.

    Laux, I. et al. Response differences between human CD4+ and CD8+ T-cells during CD28 co-stimulation: implications for immune cell-based therapies and studies related to the expansion of double-positive T-cells during aging. Clin. Immunol. 96, 187–197 (2000).

    Article  CAS  Google Scholar 

  83. 83.

    Zhang, H. et al. 4–1BB is superior to CD28 co-stimulation for generating CD8(+) cytotoxic lymphocytes for adoptive immunotherapy. J. Immunol. 179, 4910–4918 (2007).

    Article  CAS  Google Scholar 

  84. 84.

    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  Google Scholar 

  85. 85.

    Ugel, S. et al. In vivo administration of artificial antigen presenting cells activates low avidity T cells for treatment of cancer. Cancer Res. 69, 9376–9384 (2009).

    Article  CAS  Google Scholar 

  86. 86.

    Shen, C., Zhang, J., Xia, L., Meng, F. & Xie, W. Induction of tumour antigen-specific cytotoxic T cell responses in naïve mice by latex microspheres-based artificial antigen-presenting cell constructs. Cell. Immunol. 247, 28–35 (2007).

    Article  CAS  Google Scholar 

  87. 87.

    Stephan, S. B. et al. Biopolymer implants enhance the efficacy of adoptive T-cell therapy. Nat. Biotechnol. 33, 97–101 (2014).

    Article  CAS  Google Scholar 

  88. 88.

    Thelin, M. A. et al. In vivo enrichment of diabetogenic T cells. Diabetes 66, 2220–2229 (2017).

    Article  CAS  Google Scholar 

  89. 89.

    Rahimian, S. et al. Polymeric microparticles for sustained and local delivery of antiCD40 and antiCTLA-4 in immunotherapy of cancer. Biomaterials 61, 33–40 (2015).

    Article  CAS  Google Scholar 

  90. 90.

    Li, Y. et al. Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumour immunity. OncoImmunology 5, e1074374 (2016).

    Article  CAS  Google Scholar 

  91. 91.

    Wang, C. et al. In situ formed reactive oxygen species–responsive scaffold with gemcitabine and checkpoint inhibitor for combination therapy. Sci. Transl. Med. 10, eaan3682 (2018).

    Article  Google Scholar 

  92. 92.

    Wang, C. et al. In situ activation of platelets with checkpoint inhibitors for post-surgical cancer immunotherapy. Nat. Biomed. Eng. 1, 0011 (2017).

    Article  Google Scholar 

  93. 93.

    Ishihara, J. et al. Matrix-binding checkpoint immunotherapies enhance antitumour efficacy and reduce adverse events. Sci. Transl. Med. 9, eaan0401 (2017).

    Article  Google Scholar 

  94. 94.

    Wang, C. et al. Immunological responses triggered by photothermal therapy with carbon nanotubes in combination with anti-CTLA-4 therapy to inhibit cancer metastasis. Adv. Mater. 26, 8154–8162 (2014).

    Article  CAS  Google Scholar 

  95. 95.

    Duan, X. et al. Photodynamic therapy mediated by nontoxic core–shell nanoparticles synergizes with immune checkpoint blockade to elicit antitumour immunity and antimetastatic effect on breast cancer. J. Am. Chem. Soc 138, 16686–16695 (2016).

    Article  CAS  Google Scholar 

  96. 96.

    Min, Y. et al. Antigen-capturing nanoparticles improve the abscopal effect and cancer immunotherapy. Nat. Nanotech. 12, 877–882 (2017).

    Article  CAS  Google Scholar 

  97. 97.

    He, C. et al. Core-shell nanoscale coordination polymers combine chemotherapy and photodynamic therapy to potentiate checkpoint blockade cancer immunotherapy. Nat. Commun. 7, 12499 (2016).

    Article  CAS  Google Scholar 

  98. 98.

    Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article  CAS  Google Scholar 

  99. 99.

    Ali, O. A., Lewin, S. A., Dranoff, G. & Mooney, D. J. Vaccines combined with immune checkpoint antibodies promote cytotoxic T-cell activity and tumour eradication. Cancer Immunol. Res. 4, 95–100 (2016).

    Article  CAS  Google Scholar 

  100. 100.

    DPX-Survivac and checkpoint inhibitor in DLBCL. (2018).

  101. 101.

    Shimizu, T. et al. Nanogel DDS enables sustained release of IL-12 for tumour immunotherapy. Biochem. Biophys. Res. Commun. 367, 330–335 (2008).

    Article  CAS  Google Scholar 

  102. 102.

    Dow, S. W. et al. Intravenous cytokine gene delivery by lipid-DNA complexes controls the growth of established lung metastases. Hum. Gene Ther. 10, 2961–2972 (1999).

    Article  CAS  Google Scholar 

  103. 103.

    Park, J. et al. Combination delivery of TGF-β inhibitor and IL-2 by nanoscale liposomal polymeric gels enhances tumour immunotherapy. Nat. Mater. 11, 895–905 (2012).

    Article  CAS  Google Scholar 

  104. 104.

    Schmid, A. S., Tintor, D. & Neri, D. Novel antibody-cytokine fusion proteins featuring granulocyte-colony stimulating factor, interleukin-3 and interleukin-4 as payloads. J. Biotechnol. 271, 29–36 (2018).

    Article  CAS  Google Scholar 

  105. 105.

    Rekers, N. H. et al. The immunocytokine L19-IL2: An interplay between radiotherapy and long-lasting systemic antitumour immune responses. OncoImmunology 7, 1414119 (2018).

    Article  Google Scholar 

  106. 106.

    Charych, D. H. et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumour exposure, and marked efficacy in mouse tumour models. Clin. Cancer Res. 22, 680–690 (2016).

    Article  CAS  Google Scholar 

  107. 107.

    Noy, R. & Pollard Jeffrey W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    Article  CAS  Google Scholar 

  108. 108.

    Zhang, Q.-w et al. Prognostic significance of tumour-associated macrophages in solid tumour: a meta-analysis of the literature. PLOS One 7, e50946 (2012).

    Article  CAS  Google Scholar 

  109. 109.

    Sica, A. & Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. The J. Clin. Investig. 122, 787–795 (2012).

    Article  CAS  Google Scholar 

  110. 110.

    Ngambenjawong, C., Gustafson, H. H. & Pun, S. H. Progress in tumour-associated macrophage (TAM)-targeted therapeutics. Adv. Drug Deliv. Rev. 114, 206–221 (2017).

    Article  CAS  Google Scholar 

  111. 111.

    Zeisberger, S. M. et al. Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br. J. Cancer 95, 272–281 (2006).

    Article  CAS  Google Scholar 

  112. 112.

    Shen, S. et al. Spatial targeting of tumour-associated macrophages and tumour cells with a pH-sensitive cluster nanocarrier for cancer chemoimmunotherapy. Nano Lett. 17, 3822–3829 (2017).

    Article  CAS  Google Scholar 

  113. 113.

    Ernsting, M. J. et al. Targeting of metastasis-promoting tumour-associated fibroblasts and modulation of pancreatic tumour-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle. J. Control. Release 206, 122–130 (2015).

    Article  CAS  Google Scholar 

  114. 114.

    Pucci, F. et al. SCS macrophages suppress melanoma by restricting tumour-derived vesicle–B cell interactions. Science 352, 242–246 (2016).

    Article  CAS  Google Scholar 

  115. 115.

    Ohnishi, K. et al. CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. Cancer Sci. 104, 1237–1244 (2013).

    Article  CAS  Google Scholar 

  116. 116.

    Shiota, T. et al. The clinical significance of CD169-positive lymph node macrophage in patients with breast cancer. PLOS One 11, e0166680 (2016).

    Article  CAS  Google Scholar 

  117. 117.

    Wang, Y. et al. Polymeric nanoparticles promote macrophage reversal from M2 to M1 phenotypes in the tumour microenvironment. Biomaterials 112, 153–163 (2017).

    Article  CAS  Google Scholar 

  118. 118.

    Huang, Z. et al. Targeted delivery of oligonucleotides into tumour-associated macrophages for cancer immunotherapy. J. Control. Release 158, 286–292 (2012).

    Article  CAS  Google Scholar 

  119. 119.

    Zanganeh, S. et al. Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues. Nat. Nanotech. 11, 986–994 (2016).

    Article  CAS  Google Scholar 

  120. 120.

    Song, M., Liu, T., Shi, C., Zhang, X. & Chen, X. Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumour-associated macrophages toward M1-like phenotype and attenuating tumour hypoxia. ACS Nano 10, 633–647 (2016).

    Article  CAS  Google Scholar 

  121. 121.

    Shvedova, A. A. et al. Carbon nanotubes enhance metastatic growth of lung carcinoma via up‐regulation of myeloid‐derived suppressor cells. Small 9, 1691–1695 (2013).

    Article  CAS  Google Scholar 

  122. 122.

    Wesolowski, R., Markowitz, J. & Carson, W. E. Myeloid derived suppressor cells – a new therapeutic target in the treatment of cancer. J. Immunother. Cancer (2013).

  123. 123.

    Kourtis, I. C. et al. Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumours in mice. PLOS One 8, e61646 (2013).

    Article  CAS  Google Scholar 

  124. 124.

    Jeanbart, L., Kourtis, I. C., van der Vlies, A. J., Swartz, M. A. & Hubbell, J. A. 6-thioguanine-loaded polymeric micelles deplete myeloid-derived suppressor cells and enhance the efficacy of T cell immunotherapy in tumour-bearing mice. Cancer Immunol. Immunother. 64, 1033–1046 (2015).

    Article  CAS  Google Scholar 

  125. 125.

    Sasso, M. S. et al. Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy. Biomaterials 96, 47–62 (2016).

    Article  CAS  Google Scholar 

  126. 126.

    Topalian, S. L., Taube, J. M., Anders, R. A. & Pardoll, D. M. Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat. Rev. Cancer 16, 275–287 (2016).

    Article  CAS  Google Scholar 

  127. 127.

    Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  Google Scholar 

  128. 128.

    Freiburghaus, C. et al. Synergistic effects of agonistic co-stimulatory antibodies adsorbed to amphiphilic poly (γ-glutamic acid) nanoparticles. J. Immunother. Cancer 1, P128 (2013).

    Article  Google Scholar 

  129. 129.

    Mi, Y. et al. A dual immunotherapy nanoparticle improves T‐cell activation and cancer immunotherapy. Adv. Mater. 30, 1706098 (2018).

    Article  CAS  Google Scholar 

  130. 130.

    Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).

    Article  CAS  Google Scholar 

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The authors would like to acknowledge funding from the National Institutes of Health (1 R01 EB023287, 1 U01 CA214369, 1 R01 CA223255). H.W. gratefully acknowledges funding support from the Wyss Technology Development Fellowship.

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Correspondence to David J. Mooney.

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Wang, H., Mooney, D.J. Biomaterial-assisted targeted modulation of immune cells in cancer treatment. Nature Mater 17, 761–772 (2018).

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