Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges


Multiple nanotherapeutics have been approved for patients with cancer, but their effects on survival have been modest and, in some examples, less than those of other approved therapies. At the same time, the clinical successes achieved with immunotherapy have revolutionized the treatment of multiple advanced-stage malignancies. However, the majority of patients do not benefit from the currently available immunotherapies and many develop immune-related adverse events. By contrast, nanomedicines can reduce — but do not eliminate — the risk of certain life-threatening toxicities. Thus, the combination of these therapeutic classes is of intense research interest. The tumour microenvironment (TME) is a major cause of the failure of both nanomedicines and immunotherapies that not only limits delivery, but also can compromise efficacy, even when agents accumulate in the TME. Coincidentally, the same TME features that impair nanomedicine delivery can also cause immunosuppression. In this Perspective, we describe TME normalization strategies that have the potential to simultaneously promote the delivery of nanomedicines and reduce immunosuppression in the TME. Then, we discuss the potential of a combined nanomedicine-based TME normalization and immunotherapeutic strategy designed to overcome each step of the cancer-immunity cycle and propose a broadly applicable ‘minimal combination’ of therapies designed to increase the number of patients with cancer who are able to benefit from immunotherapy.

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Fig. 1: Cancer-immunity TME phenotypes affecting responsiveness to immunotherapy18.
Fig. 2: How nanomedicines can be used to perpetuate the cancer-immunity cycle.
Fig. 3: Normalizing the TME to increase the penetration of combination therapies.


  1. 1.

    Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev. Clin. Oncol. 7, 653–664 (2010).

  2. 2.

    Haslam, A. & Prasad, V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw. Open. 2, e192535–e192535 (2019).

  3. 3.

    Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158–168 (2018).

  4. 4.

    Riley, R. S., June, C. H., Langer, R. & Mitchell, M. J. Delivery technologies for cancer immunotherapy. Nat. Rev. Drug. Discovery 18, 175–196 (2019).

  5. 5.

    Goldberg, M. S. et al. Improving cancer immunotherapy through nanotechnology. Nat. Rev. Cancer 19, 587–602 (2019).

  6. 6.

    Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

  7. 7.

    Jain, R. K. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 50, 814s–819s (1990).

  8. 8.

    Chauhan, V. P. & Jain, R. K. Strategies for advancing cancer nanomedicine. Nat. Mater. 12, 958–962 (2013).

  9. 9.

    Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

  10. 10.

    Martin, J. D., Seano, G. & Jain, R. K. Normalizing function of tumor vessels: progress, opportunities and challenges. Annu. Rev. Physiol. 81, 505–534 (2019).

  11. 11.

    Fukumura, D., Kloepper, J., Amoozgar, Z., Duda, D. G. & Jain, R. K. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat. Rev. Clin. Oncol. 15, 325–340 (2018).

  12. 12.

    Lee, H. et al. 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin. Cancer Res. 23, 4190–4202 (2017).

  13. 13.

    Ramanathan, R. K. et al. Correlation between ferumoxytol uptake in tumor lesions by MRI and response to nanoliposomal irinotecan in patients with advanced solid tumors: a pilot study. Clin. Cancer Res. 23, 3638–3648 (2017).

  14. 14.

    Stylianopoulos, T., Munn, L. L. & Jain, R. K. Reengineering the physical microenvironment of tumors to improve drug delivery and efficacy: from mathematical modeling to bench to bedside. Trends Cancer 4, 292–319 (2018).

  15. 15.

    Chauhan, V. P., Stylianopoulos, T., Boucher, Y. & Jain, R. K. Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annu. Rev. Chem. Biomol. Eng. 2, 281–298 (2011).

  16. 16.

    Baine, M. K. et al. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget 6, 24990–25002 (2015).

  17. 17.

    Müller, P. et al. Metastatic spread in patients with non-small cell lung cancer is associated with a reduced density of tumor-infiltrating T cells. Cancer Immunol. Immunother. 65, 1–11 (2016).

  18. 18.

    Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer–immune set point. Nature 541, 321–330 (2017).

  19. 19.

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

  20. 20.

    Veglia, F. & Gabrilovich, D. I. Dendritic cells in cancer: the role revisited. Curr. Opin. immunol. 45, 43–51 (2017).

  21. 21.

    Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011).

  22. 22.

    Togashi, Y., Shitara, K. & Nishikawa, H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat. Rev. Clin. Oncol. 16, 356–371 (2019).

  23. 23.

    Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

  24. 24.

    Chen, I. X. et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc. Natl Acad. Sci. USA 116, 4558–4566 (2019).

  25. 25.

    Chauhan, V. P. et al. Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy. Proc. Natl Acad. Sci. USA 116, 10674–10680 (2019).

  26. 26.

    Costa, A. et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell 33, 463–479. e410 (2018).

  27. 27.

    Rytelewski, M. et al. Merger of dynamic two-photon and phosphorescence lifetime microscopy reveals dependence of lymphocyte motility on oxygen in solid and hematological tumors. J. Immunother. Cancer 7, 78 (2019).

  28. 28.

    Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 7, 277ra230 (2015).

  29. 29.

    Maenhout, S. K., Thielemans, K. & Aerts, J. L. Location, location, location: functional and phenotypic heterogeneity between tumor-infiltrating and non-infiltrating myeloid-derived suppressor cells. Oncoimmunology 3, e956579 (2014).

  30. 30.

    Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015).

  31. 31.

    Palazon, A. et al. An HIF-1α/VEGF-A axis in cytotoxic T cells regulates tumor progression. Cancer Cell 32, 669–683 (2017).

  32. 32.

    Wallin, J. J. et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat. Commun. 7, 12624 (2016).

  33. 33.

    Noman, M. Z. et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211, 781–790 (2014).

  34. 34.

    Noman, M. Z. et al. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am. J. Physiol. Cell Physiol. 309, C569–C579 (2015).

  35. 35.

    Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746–2756 (2012).

  36. 36.

    Kuczek, D. E. et al. Collagen density regulates the activity of tumor-infiltrating T cells. J. Immunother. Cancer 7, 68 (2019).

  37. 37.

    Mazzone, M. & Bergers, G. Regulation of blood and lymphatic vessels by immune cells in tumors and metastasis. Annu. Rev. Physiol. 81, 535–560 (2019).

  38. 38.

    Munn, L. L. & Jain, R. K. Vascular regulation of anti-tumor immunity. Science 365, 544–555 (2019).

  39. 39.

    Huang, Y. et al. Improving immune–vascular crosstalk for cancer immunotherapy. Nat. Rev. Immunol. 18, 195–203 (2018).

  40. 40.

    Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).

  41. 41.

    Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005).

  42. 42.

    Goel, S. et al. Normalization of the vasculature for treatment of cancer and other diseases. Physiol. Rev. 91, 1071–1121 (2011).

  43. 43.

    Carmeliet, P. & Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug. Discov. 10, 417–427 (2011).

  44. 44.

    Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013).

  45. 45.

    Viallard, C. & Larrivée, B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis 20, 409–426 (2017).

  46. 46.

    Jain, R. K., Martin, J. D. & Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014).

  47. 47.

    Whatcott, C. J., Han, H. & Von Hoff, D. D. Orchestrating the tumor microenvironment to improve survival for patients with pancreatic cancer: normalization, not destruction. Cancer J. 21, 299–306 (2015).

  48. 48.

    Stapleton, S., Allen, C., Pintilie, M. & Jaffray, D. A. Tumor perfusion imaging predicts the intra-tumoral accumulation of liposomes. J. Control. Rel. 172, 351–357 (2013).

  49. 49.

    Toy, R. et al. Multimodal in vivo imaging exposes the voyage of nanoparticles in tumor microcirculation. ACS Nano 7, 3118–3129 (2013).

  50. 50.

    Chauhan, V. P. et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7, 383–388 (2012).

  51. 51.

    Martin, J. D. et al. Dexamethasone increases cisplatin-loaded nanocarrier delivery and efficacy in metastatic breast cancer by normalizing the tumor microenvironment. ACS Nano 13, 6396–6408 (2019).

  52. 52.

    Stylianopoulos, T. & Jain, R. K. Combining two strategies to improve perfusion and drug delivery in solid tumors. Proc. Natl Acad. Sci. USA 110, 18632–18637 (2013).

  53. 53.

    Jayson, G. C., Kerbel, R., Ellis, L. M. & Harris, A. L. Antiangiogenic therapy in oncology: current status and future directions. Lancet 388, 518–529 (2016).

  54. 54.

    Chauhan, V. P. et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26, 14–15 (2014).

  55. 55.

    Stylianopoulos, T. et al. Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res. 73, 3833–3841 (2013).

  56. 56.

    Stylianopoulos, T. et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc. Natl Acad. Sci. USA 109, 15101–15108 (2012).

  57. 57.

    Papageorgis, P. et al. Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo-and nanotherapeutics in a size-independent manner. Sci. Rep. 7, 46140 (2017).

  58. 58.

    Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J. & Jain, R. K. Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60, 2497–2503 (2000).

  59. 59.

    McKee, T. D. et al. Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector. Cancer Res. 66, 2509–2513 (2006).

  60. 60.

    Brown, E. et al. Dynamic imaging of collagen and its modulation in tumors in vivo using second-harmonic generation. Nat. Med. 9, 796–800 (2003).

  61. 61.

    Mok, W., Boucher, Y. & Jain, R. K. Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus. Cancer Res. 67, 10664–10668 (2007).

  62. 62.

    Sherman, M. H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

  63. 63.

    Sheridan, C. Pancreatic cancer provides test bed for first mechanotherapeutics. Nat. Biotechnol. 37, 829 (2019).

  64. 64.

    Panagi, M. et al. TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics 10, 1910–1922 (2020).

  65. 65.

    Incio, J. et al. Metformin reduces desmoplasia in pancreatic cancer by reprogramming stellate cells and tumor-associated macrophages. PLoS One 10, e0141392 (2015).

  66. 66.

    Polydorou, C., Mpekris, F., Papageorgis, P., Voutouri, C. & Stylianopoulos, T. Pirfenidone normalizes the tumor microenvironment to improve chemotherapy. Oncotarget 8, 24506–24517 (2017).

  67. 67.

    Zhao, Y. et al. Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Proc. Natl Acad. Sci. USA 116, 2210–2219 (2019).

  68. 68.

    Liu, H. et al. Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clin. Cancer Res. 23, 5959–5969 (2017).

  69. 69.

    Geller, A. et al. Angiotensin system inhibitors during induction chemotherapy for esophageal adenocarcinoma: analysis of survival. J. Clin. Oncol. 36, e16066 (2018).

  70. 70.

    Pinter, M. et al. Use of inhibitors of the renin–angiotensin system is associated with longer survival in patients with hepatocellular carcinoma. United Eur. Gastroenterol. J. 5, 987–996 (2017).

  71. 71.

    Pinter, M. & Jain, R. K. Targeting the renin-angiotensin system to improve cancer treatment: implications for immunotherapy. Sci. Transl. Med. 9, eaan5616 (2017).

  72. 72.

    Levin, V. A., Chan, J., Datta, M., Yee, J. L. & Jain, R. K. Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab. J. Neurooncol. 134, 325–330 (2017).

  73. 73.

    Cleary, J. M. et al. FOLFOX plus ziv-aflibercept or placebo in first-line metastatic esophagogastric adenocarcinoma: a double-blind, randomized, multicenter phase 2 trial. Cancer 125, 2213–2221 (2019).

  74. 74.

    Chauhan, V. P. et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

  75. 75.

    Diop-Frimpong, B., Chauhan, V. P., Krane, S., Boucher, Y. & Jain, R. K. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc. Natl Acad. Sci. USA 108, 2909–2914 (2011).

  76. 76.

    Murphy, J. E. et al. A phase II study of neoadjuvant FOLFIRINOX in combination with losartan followed by chemoradiotherapy in locally advanced pancreatic cancer: R0 resection rate and clinical outcomes. JAMA Oncol. 5, 1020–1027 (2019).

  77. 77.

    Zheng, X. et al. Increased vessel perfusion predicts the efficacy of immune checkpoint blockade. J. Clin. Invest. 128, 2104–2115 (2018).

  78. 78.

    Allen, E. et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 9, eaak9679 (2017).

  79. 79.

    Schmittnaegel, M. et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci. Transl. Med. 9, eaak9670 (2017).

  80. 80.

    Shigeta, K. et al. Dual programmed death receptor-1 and vascular endothelial growth factor receptor-2 blockade promotes vascular normalization and enhances antitumor immune responses in hepatocellular carcinoma. Hepatology (2019).

  81. 81.

    Huang, Y. et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc. Natl Acad. Sci. USA 109, 17561–17566 (2012).

  82. 82.

    Shrimali, R. K. et al. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).

  83. 83.

    Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

  84. 84.

    Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

  85. 85.

    Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

  86. 86.

    Heist, R. S. et al. Improved tumor vascularization after anti-VEGF therapy with carboplatin and nab-paclitaxel associates with survival in lung cancer. Proc. Natl Acad. Sci. USA 112, 1547–1552 (2015).

  87. 87.

    Tian, L. et al. Mutual regulation of tumour vessel normalization and immunostimulatory reprogramming. Nature 544, 250–254 (2017).

  88. 88.

    Chakravarthy, A., Khan, L., Bensler, N. P., Bose, P. & De Carvalho, D. D. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat. Commun. 9, 4692 (2018).

  89. 89.

    Tauriello, D. V. et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538–543 (2018).

  90. 90.

    Vanpouille-Box, C. et al. TGFβ is a master regulator of radiation therapy-induced antitumor immunity. Cancer Res. 75, 2232–2242 (2015).

  91. 91.

    Medjebar, S. et al. Angiotensin-converting enzyme inhibitor prescription is associated with decreased progression-free survival (PFS) and overall survival (OS) in patients with lung cancers treated with PD-1/PD-L1 immune checkpoint blockers. J. Clin. Oncol. 37, e20512 (2019).

  92. 92.

    Regan, D. P. et al. The angiotensin receptor blocker losartan suppresses growth of pulmonary metastases via AT1R-independent inhibition of CCR2 signaling and monocyte recruitment. J. Immunol. 202, 3087–3102 (2019).

  93. 93.

    Newick, K., O'Brien, S., Moon, E. & Albelda, S. M. CAR T cell therapy for solid tumors. Annu. Rev. Med. 68, 139–152 (2017).

  94. 94.

    Segal, N. H. et al. Epitope landscape in breast and colorectal cancer. Cancer Res. 68, 889–892 (2008).

  95. 95.

    Stevanovic´, S. et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356, 200–205 (2017).

  96. 96.

    Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

  97. 97.

    Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018).

  98. 98.

    Soliman, H. H. nab-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors. Onco Targets Ther. 10, 101 (2017).

  99. 99.

    Schuler, G. & Steinman, R. Dendritic cells as adjuvants for immune-mediated resistance to tumors. J. Exp. Med. 186, 1183–1187 (1997).

  100. 100.

    Albert, M. L., Sauter, B. & Bhardwaj, N. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392, 86 (1998).

  101. 101.

    Mpekris, F., Baish, J. W., Stylianopoulos, T. & Jain, R. K. Role of vascular normalization in benefit from metronomic chemotherapy. Proc. Natl Acad. Sci. USA 114, 1994–1999 (2017).

  102. 102.

    Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).

  103. 103.

    Zsiros, E. et al. A phase II trial of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer. Gynecol. Oncol. 154, 23 (2019).

  104. 104.

    Matulonis, U. et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann. Oncol. 30, 1080–1087 (2019).

  105. 105.

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

  106. 106.

    Peng, J. et al. Photosensitizer micelles together with IDO inhibitor enhance cancer photothermal therapy and immunotherapy. Adv. Sci. 5, 1700891 (2018).

  107. 107.

    Chen, Q. et al. Nanoparticle-enhanced radiotherapy to trigger robust cancer immunotherapy. Adv. Mater. 31, 1802228 (2019).

  108. 108.

    Chen, Z. et al. Bioinspired hybrid protein oxygen nanocarrier amplified photodynamic therapy for eliciting anti-tumor immunity and abscopal effect. ACS Nano 12, 8633–8645 (2018).

  109. 109.

    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).

  110. 110.

    Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

  111. 111.

    Demaria, S. et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728–734 (2005).

  112. 112.

    Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

  113. 113.

    Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520, 373–377 (2015).

  114. 114.

    Bonvalot, S. et al. NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act. In. Sarc): a multicentre, phase 2–3, randomised, controlled trial. Lancet Oncol. 20, 1148–1159 (2019).

  115. 115.

    Liu, J. et al. TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc. Natl Acad. Sci. USA 109, 16618–16623 (2012).

  116. 116.

    Batchelor, T. T. et al. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc. Natl Acad. Sci. USA 110, 19059–19064 (2013).

  117. 117.

    Stapleton, S. et al. Radiation and heat improve the delivery and efficacy of nanotherapeutics by modulating intra-tumoral fluid dynamics. ACS Nano 12, 7583–7600 (2018).

  118. 118.

    Miller, M. A. et al. Radiation therapy primes tumors for nanotherapeutic delivery via macrophage-mediated vascular bursts. Sci. Transl. Med. 9, eaal0225 (2017).

  119. 119.

    Shamay, Y. et al. P-selectin is a nanotherapeutic delivery target in the tumor microenvironment. Sci. Transl. Med. 8, 345ra387 (2016).

  120. 120.

    Irvine, D. J., Swartz, M. A. & Szeto, G. L. Engineering synthetic vaccines using cues from natural immunity. Nat. Mater. 12, 978–990 (2013).

  121. 121.

    Ramanjulu, J. M. et al. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 564, 439–443 (2018).

  122. 122.

    Milhem, M. M. et al. Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy. J. Clin. Oncol. 37, 9534 (2019).

  123. 123.

    Meric-Bernstam, F. et al. Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas. J. Clin. Oncol. 37, 2507 (2019).

  124. 124.

    Larkin, B. et al. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J. Immunol. 199, 397–402 (2017).

  125. 125.

    Nuhn, L. et al. Nanoparticle-conjugate TLR7/8 agonist localized immunotherapy provokes safe antitumoral responses. Adv. Mater. 30, 1803397 (2018).

  126. 126.

    Wilson, D. R. et al. Biodegradable STING agonist nanoparticles for enhanced cancer immunotherapy. Nanomedicine 14, 237–246 (2018).

  127. 127.

    Koshy, S. T., Cheung, A. S., Gu, L., Graveline, A. R. & Mooney, D. J. Liposomal delivery enhances immune activation by STING agonists for cancer immunotherapy. Adv. Biosyst. 1, 1600013 (2017).

  128. 128.

    Momin, N. et al. Anchoring of intratumorally administered cytokines to collagen safely potentiates systemic cancer immunotherapy. Sci. Transl. Med. 11, eaaw2614 (2019).

  129. 129.

    Ishihara, J. et al. Targeted antibody and cytokine cancer immunotherapies through collagen affinity. Sci. Transl. Med. 11, eaau3259 (2019).

  130. 130.

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

  131. 131.

    Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).

  132. 132.

    Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).

  133. 133.

    Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013).

  134. 134.

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

  135. 135.

    Yuba, E. et al. Dextran derivative-based pH-sensitive liposomes for cancer immunotherapy. Biomaterials 35, 3091–3101 (2014).

  136. 136.

    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).

  137. 137.

    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).

  138. 138.

    Fan, Y. et al. Immunogenic cell death amplified by co-localized adjuvant delivery for cancer immunotherapy. Nano Lett. 17, 7387–7393 (2017).

  139. 139.

    Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).

  140. 140.

    Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526–1529 (2004).

  141. 141.

    Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534, 396–400 (2016).

  142. 142.

    Kanchan, V. & Panda, A. K. Interactions of antigen-loaded polylactide particles with macrophages and their correlation with the immune response. Biomaterials 28, 5344–5357 (2007).

  143. 143.

    Li, X., Sloat, B. R., Yanasarn, N. & Cui, Z. Relationship between the size of nanoparticles and their adjuvant activity: data from a study with an improved experimental design. Eur. J. Pharm. Biopharm. 78, 107–116 (2011).

  144. 144.

    Tseng, Y.-C., Xu, Z., Guley, K., Yuan, H. & Huang, L. Lipid–calcium phosphate nanoparticles for delivery to the lymphatic system and SPECT/CT imaging of lymph node metastases. Biomaterials 35, 4688–4698 (2014).

  145. 145.

    Jewell, C. M., López, S. C. B. & Irvine, D. J. In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles. Proc. Natl Acad. Sci. USA 108, 15745–15750 (2011).

  146. 146.

    Oussoren, C. & Storm, G. Liposomes to target the lymphatics by subcutaneous administration. Adv. Drug. Deliv. Rev. 50, 143–156 (2001).

  147. 147.

    Tokatlian, T. et al. Innate immune recognition of glycans targets HIV nanoparticle immunogens to germinal centers. Science 363, 649–654 (2019).

  148. 148.

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

  149. 149.

    Miao et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).

  150. 150.

    Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).

  151. 151.

    Zhang, Y., Li, N., Suh, H. & Irvine, D. J. Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity. Nat. Commun. 9, 6 (2018).

  152. 152.

    Bentebibel, S.-E. et al. A first-in-human study and biomarker analysis of NKTR-214, a novel IL2Rβγ-biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov. 9, 711–721 (2019).

  153. 153.

    Ma, L. et al. Enhanced CAR–T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365, 162–168 (2019).

  154. 154.

    Smith, T. T. et al. In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers. Nat. Nanotechnol. 12, 813–820 (2017).

  155. 155.

    Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

  156. 156.

    Harlin, H. et al. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 69, 3077–3085 (2009).

  157. 157.

    Rolny, C. et al. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell 19, 31–44 (2011).

  158. 158.

    Taggart, D. et al. Anti-PD-1/anti-CTLA-4 efficacy in melanoma brain metastases depends on extracranial disease and augmentation of CD8+ T cell trafficking. Proc. Natl Acad. Sci. USA 115, E1540–E1549 (2018).

  159. 159.

    Melder, R. J. et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 2, 992–997 (1996).

  160. 160.

    Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature 453, 410–414 (2008).

  161. 161.

    Pinter, M., Kwanten, W. J. & Jain, R. K. Renin-angiotensin system inhibitors to mitigate cancer treatment-related adverse events. Clin. Cancer Res. 24, 3803–3812 (2018).

  162. 162.

    Zhu, Y. et al. Inhibition of tumor-promoting stroma to enforce subsequently targeting AT1R on tumor cells by pathological inspired micelles. Biomaterials 161, 33–46 (2018).

  163. 163.

    Golder, M. R. et al. Reduction of liver fibrosis by rationally designed macromolecular telmisartan prodrugs. Nat. Biomed. Eng. 2, 822–830 (2018).

  164. 164.

    Han, X. et al. Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem. Nat. Commun. 9, 3390 (2018).

  165. 165.

    Huo, M. et al. Tumor-targeted delivery of sunitinib base enhances vaccine therapy for advanced melanoma by remodeling the tumor microenvironment. J. Control. Rel. 245, 81–94 (2017).

  166. 166.

    Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).

  167. 167.

    Heiss, M. M. et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int. J. Cancer 127, 2209–2221 (2010).

  168. 168.

    O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).

  169. 169.

    Choi, B. D. et al. CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity. Nat. Biotechnol. 37, 1049–1058 (2019).

  170. 170.

    Yuan, H. et al. Multivalent bi-specific nanobioconjugate engager for targeted cancer immunotherapy. Nat. Nanotechnol. 12, 763–769 (2017).

  171. 171.

    Siemens, D. R. et al. Hypoxia increases tumor cell shedding of MHC class I chain-related molecule: role of nitric oxide. Cancer Res. 68, 4746–4753 (2008).

  172. 172.

    Sethumadhavan, S. et al. Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS One 12, e0187314 (2017).

  173. 173.

    Long, G. V. et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomised, double-blind study. Lancet Oncol. 20, 1083–1097 (2019).

  174. 174.

    Krähenbühl, L. et al. A longitudinal analysis of IDO and PDL1 expression during immune- or targeted therapy in advanced melanoma. Neoplasia 20, 218–225 (2018).

  175. 175.

    Cheng, K. et al. Sequentially responsive therapeutic peptide assembling nanoparticles for dual-targeted cancer immunotherapy. Nano Lett. 18, 3250–3258 (2018).

  176. 176.

    Schmid, D. et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat. Commun. 8, 1747 (2017).

  177. 177.

    Zheng, Y., Tang, L., Mabardi, L., Kumari, S. & Irvine, D. J. Enhancing adoptive cell therapy of cancer through targeted delivery of small-molecule immunomodulators to internalizing or noninternalizing receptors. ACS Nano 11, 3089–3100 (2017).

  178. 178.

    Xu, Z., Wang, Y., Zhang, L. & Huang, L. Nanoparticle-delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment. ACS Nano 8, 3636–3645 (2014).

  179. 179.

    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).

  180. 180.

    Tang, L. et al. Enhancing T cell therapy through TCR-signaling-responsive nanoparticle drug delivery. Nat. Biotechnol. 36, 707–716 (2018).

  181. 181.

    Siriwon, N. et al. CAR-T cells surface-engineered with drug-encapsulated nanoparticles can ameliorate intratumoral T-cell hypofunction. Cancer Immunol. Res. 6, 812–824 (2018).

  182. 182.

    Terry, S. et al. Acquisition of tumor cell phenotypic diversity along the EMT spectrum under hypoxic pressure: consequences on susceptibility to cell-mediated cytotoxicity. Oncoimmunology 6, e1271858 (2017).

  183. 183.

    Karasaki, T. et al. An immunogram for the cancer-immunity cycle: towards personalized immunotherapy of lung cancer. J. Thorac. Oncol. 12, 791–803 (2017).

  184. 184.

    Nam, J. et al. Cancer nanomedicine for combination cancer immunotherapy. Nat. Rev. Mater. 4, 398–414 (2019).

  185. 185.

    Kinoh, H. et al. Nanomedicines eradicating cancer stem-like cells in vivo by pH-triggered intracellular cooperative action of loaded drugs. ACS Nano 10, 5643–5655 (2016).

  186. 186.

    Cabral, H., Miyata, K., Osada, K. & Kataoka, K. Block copolymer micelles in nanomedicine applications. Chem. Rev. 118, 6844–6892 (2018).

  187. 187.

    Duan, X. et al. Immunostimulatory nanomedicines synergize with checkpoint blockade immunotherapy to eradicate colorectal tumors. Nat. Commun. 10, 1899 (2019).

  188. 188.

    Yang, G. et al. Hollow MnO2 as a tumor-microenvironment-responsive biodegradable nano-platform for combination therapy favoring antitumor immune responses. Nat. Commun. 8, 902 (2017).

  189. 189.

    Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016).

  190. 190.

    Chiang, C.-S. et al. Combination of fucoidan-based magnetic nanoparticles and immunomodulators enhances tumour-localized immunotherapy. Nat. Nanotechnol. 13, 746–754 (2018).

  191. 191.

    Zhang, F. et al. Nanoparticles that reshape the tumor milieu create a therapeutic window for effective T cell therapy in solid malignancies. Cancer Res. 78, 3718–3730 (2018).

  192. 192.

    Miura, Y. et al. Cyclic RGD-linked polymeric micelles for targeted delivery of platinum anticancer drugs to glioblastoma through the blood–brain tumor barrier. ACS Nano 7, 8583–8592 (2013).

  193. 193.

    Quader, S. et al. cRGD peptide-installed epirubicin-loaded polymeric micelles for effective targeted therapy against brain tumors. J. Control. Release 258, 56–66 (2017).

  194. 194.

    Wong, C. et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc. Natl Acad. Sci. USA 108, 2426–2431 (2011).

  195. 195.

    Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

  196. 196.

    Arvanitis, C. D. et al. Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood–tumor barrier disruption. Proc. Natl Acad. Sci. USA 115, E8717–E8726 (2018).

  197. 197.

    Mi, P. et al. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat. Nanotechnol. 11, 724–730 (2016).

  198. 198.

    Kulkarni, A. et al. Reporter nanoparticle that monitors its anticancer efficacy in real time. Proc. Natl Acad. Sci. USA 113, E2104–E2113 (2016).

  199. 199.

    Uchida, S. et al. Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety. Biomaterials 82, 221–228 (2016).

  200. 200.

    Wang, H.-X. et al. Nonviral gene editing via CRISPR/Cas9 delivery by membrane-disruptive and endosomolytic helical polypeptide. Proc. Natl Acad. Sci. USA 115, 4903–4908 (2018).

  201. 201.

    Charlesworth, C. T. et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat. Med. 25, 249–254 (2019).

  202. 202.

    Glass, Z., Lee, M., Li, Y. & Xu, Q. Engineering the delivery system for CRISPR-based genome editing. Trends Biotechnol. 36, 173–185 (2018).

  203. 203.

    Song, W. et al. Synergistic and low adverse effect cancer immunotherapy by immunogenic chemotherapy and locally expressed PD-L1 trap. Nat. Commun. 9, 2237 (2018).

  204. 204.

    Jadidi-Niaragh, F. et al. CD73 specific siRNA loaded chitosan lactate nanoparticles potentiate the antitumor effect of a dendritic cell vaccine in 4T1 breast cancer bearing mice. J. Control. Release 246, 46–59 (2017).

  205. 205.

    Deng, Z. J. et al. Layer-by-layer nanoparticles for systemic codelivery of an anticancer drug and siRNA for potential triple-negative breast cancer treatment. ACS Nano 7, 9571–9584 (2013).

  206. 206.

    Zhao, Y. et al. Polymetformin combines carrier and anticancer activities for in vivo siRNA delivery. Nat. Commun. 7, 11822 (2016).

  207. 207.

    Kataoka, K. et al. Spontaneous formation of polyion complex micelles with narrow distribution from antisense oligonucleotide and cationic block copolymer in physiological saline. Macromolecules 29, 8556–8557 (1996).

  208. 208.

    Christie, R. J. et al. Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection. ACS Nano 6, 5174–5189 (2012).

  209. 209.

    Kim, H. J. et al. Multifunctional polyion complex micelle featuring enhanced stability, targetability, and endosome escapability for systemic siRNA delivery to subcutaneous model of lung cancer. Drug. Deliv. Transl. Res. 4, 50–60 (2014).

  210. 210.

    Nishida, H. et al. Systemic delivery of siRNA by actively targeted polyion complex micelles for silencing the E6 and E7 human papillomavirus oncogenes. J. Control. Release 231, 29–37 (2016).

  211. 211.

    Watanabe, S. et al. In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers. Nat. Commun. 10, 1894 (2019).

  212. 212.

    Jiang, H. et al. New path to treating pancreatic cancer: TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment. J. Control. Release 286, 254–263 (2018).

  213. 213.

    Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

  214. 214.

    Setten, R. L., Rossi, J. J. & Han, S. P. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 18, 421–446 (2019).

  215. 215.

    Singh, A., Trivedi, P. & Jain, N. K. Advances in siRNA delivery in cancer therapy. Artif. Cells Nanomed. Biotechnol. 46, 274–283 (2018).

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The authors apologize to authors whose work could not be cited owing to space constraints. In general, the authors focused on systemically and locally administered particle-based therapies, so the scope of this article does not include certain nanotechnologies developed for the delivery of immunotherapies, such as injectable scaffolds, which are currently under clinical investigation (NCT01753089). The authors thank M. Kalli (University of Cyprus) for assistance with the preparation of the figures, K. Kakimi (University of Tokyo) for helpful discussions and A. Osada (NanoCarrier Co., Ltd), Y. Huang (Cyrus Tang Haematology Center), M. R. Martin (University of Tokyo), V. Melo (University of Tokyo) and Z. Amoozgar and D. Fukumura (Massachusetts General Hospital) for critical input into the manuscript. The research leading to these results has received funding from the National Foundation for Cancer Research, the Ludwig Center at Harvard, the Jane’s Trust Foundation, the Advanced Medical Research Foundation, the US National Cancer Institute grants P01-CA080124, R01-CA098706, R01-CA208205 and U01-CA224348 and the US Department of Defense Breast Cancer Research Program Innovator Award W81XWH-10-1-0016 (to R.K.J.), the European Research Council grant 838414 and the INFRASTRUCTURE/1216/0052 grant co-financed by the European Regional Development Fund and the Republic of Cyprus through the Research Promotion Foundation (to T.S.), and the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research B (JP16H03179) and Young Scientists B (JP25750172) to H.C. R.K.J. is a recipient of an Outstanding Investigator Award R35-CA197743 from the U.S. National Cancer Institute. J.D.M was supported by a JSPS Postdoctoral Fellowship, P16731.

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J.D.M. researched data for this article. All authors made a substantial contribution to the discussion of content, writing the manuscript and reviewing and/or editing the manuscript prior to submission.

Correspondence to Triantafyllos Stylianopoulos or Rakesh K. Jain.

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Competing interests

J.D.M. became a full-time employee of NanoCarrier during the preparation of this manuscript. R.K.J. has received honoraria from Amgen, has acted as a consultant for Chugai, Merck, Ophthotech, Pfizer, SPARC, SynDevRx and XTuit, owns equity in Enlight, Ophthotech and SynDevRx and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. H.C. and T.S. declare no competing interests.

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Martin, J.D., Cabral, H., Stylianopoulos, T. et al. Improving cancer immunotherapy using nanomedicines: progress, opportunities and challenges. Nat Rev Clin Oncol 17, 251–266 (2020).

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