The TRPM7 inhibitor carvacrol suppresses angiogenesis and vasculogenic mimicry in triple-negative breast cancer.

Vasculogenic mimicry (VM) contributes significantly to tumor aggressiveness and resistance to anti-angiogenic therapies. Simultaneous inhibition of both angiogenesis and VM represents a promising strategy to improve therapeutic outcomes in aggressive cancers, such as triple-negative breast cancer (TNBC), which responds poorly to anti-angiogenic therapies. In this study, we identified carvacrol, a natural monoterpenoid phenol widely used as a food additive, as a dual inhibitor of angiogenesis and VM in TNBC. Carvacrol preferentially inhibited angiogenesis in endothelial cells (ECs) and VM in TNBC cells at concentrations that had minimal effects on TNBC cell proliferation. Mechanistically, carvacrol directly bound to the vanilloid-like (VL) site of transient receptor potential melastatin 7 (TRPM7), thereby inhibiting channel activity and attenuating Zn2+ influx. This triggered dephosphorylation of the mammalian target of rapamycin (mTOR) and subsequent proteasomal and lysosomal degradation of key receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), Tie2, fibroblast growth factor receptor 1 (FGFR1), and insulin-like growth factor 1 receptor (IGF1R) in ECs, as well as FGFR1 and IGF1R in TNBC cells. Genetic knockdown of TRPM7 recapitulated the anti-vascular effects and signaling alterations induced by carvacrol. In vivo, carvacrol effectively suppressed TNBC vascularization and growth in a mouse dorsal skinfold chamber model and an orthotopic xenograft model. Together, these findings suggest that carvacrol preferentially targets angiogenesis and VM in TNBC by suppressing the TRPM7/Zn2+/mTOR/RTKs axis, highlighting it as a promising therapeutic candidate for TNBC and potentially other tumors resistant to anti-angiogenic therapies, while positioning the TRPM7 channel as a novel anti-vascular target for TNBC treatment.