Terbinafine prevents colorectal cancer growth by inducing dNTP starvation and reducing immune suppression

Existing evidence indicates that gut fungal dysbiosis might play a key role in the pathogenesis of colorectal cancer (CRC). We sought to explore whether reversing the fungal dysbiosis by ter-binafine, an approved antifungal drug, might inhibit the devel-opment of CRC. A population-based study from Sweden iden-tified a total of 185 patients who received terbinafine after their CRC diagnosis and found that they had a decreased risk of death (hazard ratio = 0.50) and metastasis (hazard ratio = 0.44) compared with patients without terbinafine administra-tion. In multiple mouse models of CRC, administration of ter-binafine decreased the fungal load, the fungus-induced myeloid-derived suppressor cell (MDSC) expansion, and the tumor burden. Fecal microbiota transplantation from mice without terbinafine treatment reversed MDSC infiltration and partially restored tumor proliferation. Mechanistically, terbinafine directly impaired tumor cell proliferation by reducing the ratio of nicotinamide adenine dinucleotide phos-phate (NADP+) to reduced form of nicotinamide adenine dinu-cleotide phosphate (NADPH), suppressing the activity of glucose-6-phosphate dehydrogenase (G6PD), resulting in nucleotide synthesis disruption, deoxyribonucleotide (dNTP) starvation, and cell-cycle arrest. Collectively, terbinafine can inhibit CRC by reversing fungal dysbiosis, suppressing tumor cell proliferation, inhibiting fungus-induced MDSC infiltra-tion, and restoring antitumor immune response.

Automated summary

Research suggests that reversing gut fungal dysbiosis with terbinafine can inhibit the development of colorectal cancer (CRC). Terbinafine reduces fungal load, suppresses tumor cell proliferation, inhibits fungus-induced myeloid-derived suppressor cell expansion, and restores antitumor immune response.