The exact mechanisms are not fully understood, but as described above decreased interstitial pH in the tumor microenvironment, probably largely as a consequence of lactate production by tumors, is thought to increase activation of extracellular proteases like matrix metalloproteinases and cathepsins [51] and to reduce immunologic responses, in part through up-regulation of PD-L1 [15,52,53]. This evidence concerns the gene CTSS and neoplasm.