Here, by applying a multidisciplinary approach to a tailored in vitro/ex vivo preclinical platform, we demonstrate that pharmacological activation of TRPM8 in primary and hormone naïve metastatic models of PCa sensitizes prostate cancer cells to standard-of-care clinical protocols for the treatment of locally advanced PCa, thus pointing out the relevance of ion channels as therapeutic targets in oncology. This evidence concerns the gene TRPM8 and Familial prostate cancer.