Targeting FROUNT with Disulfiram Regulates Macrophage Responses in Cancer

Tumor-associated macrophages influence tumor progression and resistance to immune checkpoint therapy. Chemokine signaling is a key regulator of macrophage accumulation and activity. Here, we report that the chemokine receptor-binding protein FROUNT modulates tumor-associated macrophage responses and is an important regulator of tumor progression. By screening 131,200 compounds, we identified the anti-alcoholism drug disulfiram (DSF) as a potent inhibitor of FROUNT that interferes with FROUNT-chemokine receptor interaction by directly binding to FROUNT. Both DSF-treatment and FROUNT-deficiency markedly reduced tumor progression and decreased the tumor-promoting activity of macrophages. Studies using clinical specimens and FROUNT-GFP reporter mice showed that FROUNT was highly expressed in macrophages, and myeloid-specific deletion of FROUNT impaired tumor growth. Low FROUNT expression in patients with lung adenocarcinoma was correlated with better clinical outcomes. Moreover, co-treatment of DSF with an immune checkpoint antibody synergistically inhibited tumor growth. Together, inhibition of FROUNT by DSF presents a strategy for macrophage-targeted cancer therapy.