Pancreatic cancer is the 5th leading cause of death among human cancers and is characterized by poor prognosis. It has been reported that expression of certain ion channels is enhanced in pancreatic cancer cells, including the TRPM7 channel. However, while TRPM7 is reported to be involved in the malignancy of pancreatic cancer, the detailed mechanism has not yet been clarified. Here, we show that TRPM7 induces the progression of pancreatic ductal adenocarcinoma (PDAC). We found that alkaline conditions, which mimic pancreatic duct environment, enhance proliferation in PDAC cells. Notably, CRISPR-Cas9-based TRPM7 knockout abolished alkaline-induced currents and intracellular Ca2+ influx, resulting in the suppression of alkaline-induced proliferation in PDAC cells. In genetically engineered mouse models of pancreatic cancer (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre), pancreas-specific knockout of Trpm7 prolonged survival of the mice. Thus, these findings reveal an alkaline defense program involving TRPM7 that could be exploited for targeted pancreatic cancer therapies.