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.

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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.

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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


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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.

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