CASP3 and neoplasm: Acidification of the TME due to enhanced production of lactate also induces polarization of macrophages toward M2 immunosuppressive tumor-associated macrophages which further contribute to the development of resistance to gemcitabine via inhibition of caspase-3 mediated therapy-induced apoptosis [118] and decreased gemcitabine uptake by tumor cells associated with a release of pyrimidines [119], at the same time it enhances the development and maintenance of a squamous PDAC phenotype [59].