Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties

Nat Commun. 2020 Jan 30;11(1):609. doi: 10.1038/s41467-020-14338-5.


Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Chemokines / metabolism
  • Clathrin Heavy Chains / metabolism*
  • Disease Progression
  • Disulfiram / pharmacology*
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Immunotherapy
  • Kinetics
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology*
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Neoplasm Metastasis
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism*
  • Prognosis
  • Risk Factors


  • Chemokines
  • FROUNT protein, mouse
  • NUP85 protein, human
  • Nuclear Pore Complex Proteins
  • Clathrin Heavy Chains
  • Disulfiram