Checkpoint blockade immunotherapy relies on energized cytotoxic T cells attacking tumour tissue systemically. However, for many cancers, the reliance on T cell infiltration leads to low response rates. Conversely, radiotherapy has served as a powerful therapy for local tumours over the past 100 years, yet is rarely sufficient to cause systemic tumour rejection. Here, we describe a treatment strategy that combines nanoscale metal–organic framework (nMOF)-enabled radiotherapy–radiodynamic therapy with checkpoint blockade immunotherapy for both local and systemic tumour elimination. In mouse models of breast and colorectal cancer, intratumorally injected nMOFs treated with low doses of X-ray irradiation led to the eradication of local tumours and, when loaded with an inhibitor of the immune checkpoint molecule indoleamine 2,3-dioxygenase, the irradiated nMOFs led to consistent abscopal responses that rejected distal tumours. By combining the advantages of local radiotherapy and systemic tumour rejection via synergistic X-ray-induced in situ vaccination and indoleamine 2,3-dioxygenase inhibition, nMOFs may overcome some of the limitations of checkpoint blockade in cancer treatment.
Subscribe to Journal
Get full journal access for 1 year
only $8.67 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Couzin-Frankel, J. Cancer immunotherapy. Science 342, 1432–1433 (2013).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).
Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nat. Med. 10, 909–915 (2004).
Postow, M. A., Callahan, M. K. & Wolchok, J. D. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33, 1974–1982 (2015).
Bentzen, S. M. Preventing or reducing late side effects of radiation therapy: radiobiology meets molecular pathology. Nat. Rev. Cancer 6, 702–713 (2006).
Timmerman, R. et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA 303, 1070–1076 (2010).
Whelan, T. J. et al. Long-term results of hypofractionated radiation therapy for breast cancer. N. Engl. J. Med. 362, 513–520 (2010).
Barnett, G. C. et al. Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype. Nat. Rev. Cancer 9, 134–142 (2009).
Formenti, S. C. & Demaria, S. Systemic effects of local radiotherapy. Lancet Oncol. 10, 718–726 (2009).
Barker, H. E., Paget, J. T., Khan, A. A. & Harrington, K. J. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat. Rev. Cancer 15, 409–425 (2015).
Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).
Shahabi, V., Postow, M. A., Tuck, D. & Wolchok, J. D. Immune-priming of the tumor microenvironment by radiotherapy: rationale for combination with immunotherapy to improve anticancer efficacy. Am. J. Clin. Oncol. 38, 90–97 (2015).
Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. & Wolchok, J. D. Immune modulation in cancer with antibodies. Annu. Rev. Med. 65, 185–202 (2014).
Formenti, S. C. & Demaria, S. Combining radiotherapy and cancer immunotherapy: a paradigm shift. J. Natl. Cancer Inst. 105, 256–265 (2013).
Dougherty, T. J. et al. Photodynamic therapy. J. Natl. Cancer Inst. 90, 889–905 (1998).
Castano, A. P., Mroz, P. & Hamblin, M. R. Photodynamic therapy and anti-tumour immunity. Nat. Rev. Cancer 6, 535–545 (2006).
Garg, A. D., Nowis, D., Golab, J. & Agostinis, P. Photodynamic therapy: illuminating the road from cell death towards anti-tumour immunity. Apoptosis 15, 1050–1071 (2010).
Stolik, S., Delgado, J., Perez, A. & Anasagasti, L. Measurement of the penetration depths of red and near infrared light in human “ex vivo” tissues. J. Photochem. Photobiol. B Biol. 57, 90–93 (2000).
Hashiguchi, S. et al. Acridine orange excited by low-dose radiation has a strong cytocidal effect on mouse osteosarcoma. Oncology 62, 85–93 (2002).
Wang, C. et al. Synergistic assembly of heavy metal clusters and luminescent organic bridging ligands in metal–organic frameworks for highly efficient X-ray scintillation. J. Am. Chem. Soc. 136, 6171–6174 (2014).
Mellor, A. L. & Munn, D. H. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat. Rev. Immunol. 4, 762–774 (2004).
Katz, J. B., Muller, A. J. & Prendergast, G. C. Indoleamine 2,3‐dioxygenase in T‐cell tolerance and tumoral immune escape. Immunol. Rev. 222, 206–221 (2008).
Munn, D. H. et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281, 1191–1193 (1998).
Munn, D. H. et al. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189, 1363–1372 (1999).
Okamoto, A. et al. Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. Clin. Cancer Res. 11, 6030–6039 (2005).
Brandacher, G. et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin. Cancer Res. 12, 1144–1151 (2006).
Liu, X. et al. Selective inhibition of IDO1 effectively regulates mediators of antitumour immunity. Blood 115, 3520–3530 (2010).
Platten, M., von Knebel Doeberitz, N., Oezen, I., Wick, W. & Ochs, K. Cancer immunotherapy by targeting IDO1/TDO and their downstream effectors. Front. Immunol. 5, 673 (2014).
Mautino, M. R. et al. Synergistic antitumor effects of combinatorial immune checkpoint inhibition with anti-PD-1/PD-L antibodies and the IDO pathway inhibitors NLG-919 and indoximod in the context of active immunotherapy. Cancer Res. 74, 5023 (2014).
Li, M. et al. The indoleamine 2,3-dioxygenase pathway controls complement-dependent enhancement of chemo-radiation therapy against murine glioblastoma. J. Immunother. Cancer 2, 21 (2014).
Zhuang, J. et al. Optimized metal–organic-framework nanospheres for drug delivery: evaluation of small-molecule encapsulation. ACS Nano 8, 2812–2819 (2014).
McKinlay, A. C. et al. Exceptional behavior over the whole adsorption−storage−delivery cycle for NO in porous metal organic frameworks. J. Am. Chem. Soc. 130, 10440–10444 (2008).
Furukawa, H., Cordova, K. E., O’Keeffe, M. & Yaghi, O. M. The chemistry and applications of metal−organic frameworks. Science 341, 1230444 (2013).
He, C., Liu, D. & Lin, W. Nanomedicine applications of hybrid nanomaterials built from metal–ligand coordination bonds: nanoscale metal–organic frameworks and nanoscale coordination polymers. Chem. Rev. 115, 11079–11108 (2015).
Levine, D. J. et al. Olsalazine-based metal–organic frameworks as biocompatible platforms for H2 adsorption and drug delivery. J. Am. Chem. Soc. 138, 10143–10150 (2016).
Morris, W., Briley, W. E., Auyeung, E., Cabezas, M. D. & Mirkin, C. A. Nucleic acid–metal organic framework (MOF) nanoparticle conjugates. J. Am. Chem. Soc. 136, 7261–7264 (2014).
Allen, T. M. & Cullis, P. R. Drug delivery systems: entering the mainstream. Science 303, 1818–1822 (2004).
Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).
Jiang, W. et al. Designing nanomedicine for immuno-oncology. Nat. Biomed. Eng. 1, 0029 (2017).
Lovell, J. F. et al. Porphysome nanovesicles generated by porphyrin bilayers for use as multimodal biophotonic contrast agents. Nat. Mater. 10, 324–332 (2011).
Ng, K. K. & Zheng, G. Molecular interactions in organic nanoparticles for phototheranostic applications. Chem. Rev. 115, 11012–11042 (2015).
Carter, K. A. et al. Porphyrin–phospholipid liposomes permeabilized by near-infrared light. Nat. Commun. 5, 3546 (2014).
Wang, A. Z., Langer, R. & Farokhzad, O. C. Nanoparticle delivery of cancer drugs. Annu. Rev. Med. 63, 185–198 (2012).
Lu, K., He, C. & Lin, W. Nanoscale metal–organic framework for highly effective photodynamic therapy of resistant head and neck cancer. J. Am. Chem. Soc. 136, 16712–16715 (2014).
Dai, R. et al. Electron crystallography reveals atomic structures of metal–organic nanoplates with M12 (μ3-O)8(μ3-OH)8(μ2-OH)6 (M = Zr, Hf) secondary building units. Inorg. Chem. 56, 8128–8134 (2017).
Cliffe, M. J. et al. Metal–organic nanosheets formed via defect-mediated transformation of a hafnium metal–organic framework. J. Am. Chem. Soc. 139, 5397–5404 (2017).
Tourneau, C. L. et al. A phase 1 trial of NBTXR3 nanoparticles activated by intensity-modulated radiation therapy (IMRT) in the treatment of advanced-stage head and neck squamous cell carcinoma (HNSCC). J. Clin. Oncol. 35, 6080 (2017).
Lu, K. et al. Chlorin-based nanoscale metal–organic framework systemically rejects colorectal cancers via synergistic photodynamic therapy and checkpoint blockade immunotherapy. J. Am. Chem. Soc. 138, 12502–12510 (2016).
Morris, W. et al. Synthesis, structure, and metalation of two new highly porous zirconium metal–organic frameworks. Inorg. Chem. 51, 6443–6445 (2012).
Sheridan, C. Proof of concept for next-generation nanoparticle drugs in humans. Nat. Biotechnol. 30, 471–473 (2012).
Seiwert, T. Y., Salama, J. K. & Vokes, E. E. The concurrent chemoradiation paradigm—general principles. Nat. Clin. Pract. Oncol. 4, 86–100 (2007).
Fowler, J. Fractionated radiation therapy after Strandqvist. Acta Radiol. Oncol. 23, 209–216 (1984).
He, J. et al. The induction of partial resistance to photodynamic therapy by the protooncogene BCL‐2. Photochem. Photobiol. 64, 845–852 (1996).
Yue, E. W. et al. Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model. J. Med. Chem. 52, 7364–7367 (2009).
Beatty, G. L. et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin. Cancer Res. 23, 3269–3276 (2017).
Nelson, B. H. CD20+ B cells: the other tumor-infiltrating lymphocytes. J. Immunol. 185, 4977–4982 (2010).
Tsou, P., Katayama, H., Ostrin, E. J. & Hanash, S. M. The emerging role of B cells in tumor immunity. Cancer Res. 76, 5597–5601 (2016).
Garnelo, M. et al. Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma. Gut 66, 342–351 (2017).
Weinstein, J. R. et al. IgM-dependent phagocytosis in microglia is mediated by complement receptor 3, not Fc⍺/μ receptor. J. Immunol. 195, 5309–5317 (2015).
Wang, H., Coligan, J. E. & Morse, H. C. 3rd Emerging functions of natural IgM and its Fc receptor FCMR in immune homeostasis. Front. Immunol. 7, 99 (2016).
Chen, H. et al. Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment. Nano Lett. 15, 2249–2256 (2015).
Siva, S., MacManus, M. P., Martin, R. F. & Martin, O. A. Abscopal effects of radiation therapy: a clinical review for the radiobiologist. Cancer Lett. 356, 82–90 (2015).
Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat. Rev. 41, 503–510 (2015).
Wei, W. Z. et al. Concurrent induction of antitumour immunity and autoimmune thyroiditis in CD4+CD25+ regulatory T cell-depleted mice. Cancer Res. 65, 8471–8478 (2005).
We thank C. Poon and Z. Lin for experimental help. We also thank S. J. Kron and M. S. Lesniak for kindly providing the cell lines. We acknowledge the National Cancer Institute (U01–CA198989 and R21-CA195075A), University of Chicago Medicine Comprehensive Cancer Center (NIH CCSG: P30 CA014599), Chemistry–Biology Interface training grant (NIH 5T32GM008720-15) and Ludwig Center for Metastasis Research for funding support.
W.L. is the founder of RiMO Therapeutics, which licensed the RT–RDT technology from The University of Chicago. R.R.W. is an advisor to RiMO Therapeutics.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Lu, K., He, C., Guo, N. et al. Low-dose X-ray radiotherapy–radiodynamic therapy via nanoscale metal–organic frameworks enhances checkpoint blockade immunotherapy. Nat Biomed Eng 2, 600–610 (2018). https://doi.org/10.1038/s41551-018-0203-4
Nano Research (2020)
Advanced Functional Materials (2020)
Self-assembled CeVO4/Au heterojunction nanocrystals for photothermal/photoacoustic bimodal imaging-guided phototherapy
RSC Advances (2020)
ACS Applied Materials & Interfaces (2020)