In the present study, we provide evidence that, TRPM7 (i) is aberrantly expressed in lung cancer tissue samples and cell lines, (ii) is an independent indicator of poor prognosis in lung cancer, and (iii) regulates the CSCs activities of lung cancer cells by modulating the Hsp90α/uPA/MMP2 signaling pathway, while its molecular or therapeutic inhibition (iv) suppresses the viability as well as metastatic and CSCs phenotypes of human lung cancer cells, and (vi) enhances the anticancer effect of standard chemotherapeutics. The gene discussed is MMP2; the disease is lung cancer.