Effectively activating macrophages that can ‘eat’ cancer cells is challenging. In particular, cancer cells secrete macrophage colony stimulating factor (MCSF), which polarizes tumour-associated macrophages from an antitumour M1 phenotype to a pro-tumorigenic M2 phenotype. Also, cancer cells can express CD47, a ‘don’t eat me’ signal that ligates with the signal regulatory protein alpha (SIRPα) receptor on macrophages to prevent phagocytosis. Here, we show that a supramolecular assembly consisting of amphiphiles inhibiting the colony stimulating factor 1 receptor (CSF-1R) and displaying SIRPα-blocking antibodies with a drug-to-antibody ratio of 17,000 can disable both mechanisms. The supramolecule homes onto SIRPα on macrophages, blocking the CD47–SIRPα signalling axis while sustainedly inhibiting CSF-1R. The supramolecule enhances M2-to-M1 repolarization within the tumour microenvironment, and significantly improves antitumour and antimetastatic efficacies in two aggressive animal models of melanoma and breast cancer, with respect to clinically available small-molecule and biologic inhibitors of CSF-1R signalling. Simultaneously blocking the CD47–SIRPα and MCSF–CSF-1R signalling axes may constitute a promising immunotherapy.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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


  1. 1.

    Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

  2. 2.

    Engblom, C., Pfirschke, C., & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016).

  3. 3.

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

  4. 4.

    Condeelis, J., & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

  5. 5.

    Gabrilovich, D. I., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat. Rev. Immunol. 12, 253–268 (2012).

  6. 6.

    Grivennikov, S. I., Greten, F. R., & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  7. 7.

    Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat. Immunol. 11, 889–896 (2010).

  8. 8.

    Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

  9. 9.

    Sica, A. et al. Macrophage polarization in tumour progression. Sem. Cancer Biol. 18, 349–355 (2008).

  10. 10.

    Qian, B. Z. & Pollard, J. W. Macrophage diversity enhances tumor progression and metastasis. Cell 141, 39–51 (2010).

  11. 11.

    Ruffell, B. & Coussens, L. M. Macrophages and therapeutic resistance in cancer. Cancer Cell 27, 462–472 (2015).

  12. 12.

    Ries, C. H. et al. Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. Cancer Cell 25, 846–859 (2014).

  13. 13.

    Pyonteck, S. M. et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat. Med. 19, 1264–1272 (2013).

  14. 14.

    Chao, M. P., Weissman, I. L. & Majeti, R. The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications. Curr. Opin. Immunol. 24, 225–232 (2012).

  15. 15.

    McCracken, M. N., Cha, A. C. & Weissman, I. L. Molecular pathways: activating T cells after cancer cell phagocytosis from blockade of CD47 “don’t eat me” signals. Clin. Cancer Res. 21, 3597–3601 (2015).

  16. 16.

    Beck, A., Goetsch, L., Dumontet, C. & Corvaia, N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat. Rev. Drug Discov. 16, 315–337 (2017).

  17. 17.

    Garber, K. Bispecific antibodies rise again. Nat. Rev. Drug Discov. 13, 799–801 (2014).

  18. 18.

    Kulkarni, A. et al. Algorithm for designing nanoscale supramolecular therapeutics with increased anticancer efficacy. ACS Nano 10, 8154–8168 (2016).

  19. 19.

    Kulkarni, A., Natarajan, S. K., Chandrasekar, V., Pandey, P. R. & Sengupta, S. Combining immune checkpoint inhibitors and kinase-inhibiting supramolecular therapeutics for enhanced anticancer efficacy. ACS Nano 10, 9227–9242 (2016).

  20. 20.

    Kulkarni, A. A. et al. Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy. Cancer Res. 73, 6987–6997 (2013).

  21. 21.

    Zhou, D. et al. Macrophage polarization and function with emphasis on the evolving roles of coordinated regulation of cellular signaling pathways. Cell. Signal. 26, 192–197 (2014).

  22. 22.

    Wilson, H. M. SOCS proteins in macrophage polarization and function. Front. Immunol. 5, 357, (2014).

  23. 23.

    Ruffell, B., Affara, N. I. & Coussens, L. M. Differential macrophage programming in the tumor microenvironment. Trends Immunol. 33, 119–126 (2012).

  24. 24.

    Whyte, C. S. et al. Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J. Leukoc. Biol. 90, 845–854 (2011).

  25. 25.

    Genin, M., Clement, F., Fattaccioli, A., Raes, M. & Michiels, C. M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide. BMC Cancer 15, 577 (2015).

  26. 26.

    Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014–1022 (2013).

  27. 27.

    Ruffell, B. et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell 26, 623–637 (2014).

  28. 28.

    Diamantis, N. & Banerji, U. Antibody-drug conjugates–an emerging class of cancer treatment. Br. J. Cancer 114, 362–367 (2016).

  29. 29.

    Goldman, A. et al. Rationally designed 2-in-1 nanoparticles can overcome adaptive resistance in cancer. ACS Nano 10, 5823–5834 (2016).

  30. 30.

    Sengupta, S. Cancer nanomedicine: lessons for immuno-oncology. Trends Cancer 3, 551–560 (2017).

  31. 31.

    Gholamin, S. et al. Disrupting the CD47-SIRPà anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci. Transl. Med. 9, eaaf2968 (2017).

  32. 32.

    Long, G. V. et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 18, 1202–1210 (2017).

Download references


This work was supported by a DoD Breakthrough Award (BC132168), an American Lung Association Innovation Award (LCD-259932-N), and an NCI UO1 (CA214411) to S.S. and a National Cancer Institute of the National Institutes of Health (P50CA168504) and Hearst Foundation/Brigham and Women’s Hospital Young Investigator Award to A.K. The authors would like to thank the Dana Farber Cancer Institute Flow Cytometry Core Facility for their expertise, consulting and assistance with flow cytometry experiments. The authors would like to thank the Mass Spectrometry Core Facility and Biophysical Characterization Core Facility at the Institute for Applied Life Sciences (IALS), University of Massachusetts Amherst for consultation and assistance with mass spectrometry experiments.

Author information

Author notes

  1. These authors contributed equally: Vineethkrishna Chandrasekar, Siva Kumar Natarajan.


  1. Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Ashish Kulkarni
    • , Vineethkrishna Chandrasekar
    • , Siva Kumar Natarajan
    • , Jayashree Nirgud
    • , Harshangda Bhatnagar
    • , Driti Ashok
    • , Amrendra Kumar Ajay
    •  & Shiladitya Sengupta
  2. Department of Chemical Engineering, University of Massachusetts, Amherst, MA, USA

    • Ashish Kulkarni
    •  & Anujan Ramesh
  3. Center for Bioactive Delivery, Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, USA

    • Ashish Kulkarni
  4. India Innovation Research Center, Invictus Oncology, New Delhi, India

    • Prithvi Pandey
  5. Dana Farber Cancer Institute, Boston, MA, USA

    • Shiladitya Sengupta
  6. Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA

    • Shiladitya Sengupta


  1. Search for Ashish Kulkarni in:

  2. Search for Vineethkrishna Chandrasekar in:

  3. Search for Siva Kumar Natarajan in:

  4. Search for Anujan Ramesh in:

  5. Search for Prithvi Pandey in:

  6. Search for Jayashree Nirgud in:

  7. Search for Harshangda Bhatnagar in:

  8. Search for Driti Ashok in:

  9. Search for Amrendra Kumar Ajay in:

  10. Search for Shiladitya Sengupta in:


A.K. conceived the idea, designed the experiments and mentored the research. P.P. performed the molecular dynamics simulation studies. V.C., S.K.N. and A.R. performed the supramolecule synthesis and characterization. V.C., S.K.N., A.R., J.N., H.B. and D.A. performed in vitro experiments. A.K.A. helped with confocal imaging. A.K., V.C., S.K.N. and A.R. performed in vivo experiments. A.K. and S.S. wrote the paper and received comments and edits from all the authors.

Competing interests

S.S. is a cofounder and holds equity in Akamara Therapeutics, which is developing supramolecular therapeutics, and holds equity in Mitra Biotech, which is developing cancer diagnostics.

Corresponding authors

Correspondence to Ashish Kulkarni or Shiladitya Sengupta.

Supplementary information

  1. Supplementary information

    Supplementary methods, figures and tables.

  2. Reporting Summary

About this article

Publication history






Further reading