Although these studies[45–47] and more recent ones by Rapozzi et al.[48] clearly established that NO can antagonize PDT, several key questions were left largely unsettled, which include: (1) whether this NO is generated by tumor cells per se, proximal endothelial cells, macrophages, fibroblasts, or possibly all of these; (2) which NOS isoform plays a dominant role in any given tumor; (3) whether the NOS/NO in question acts at a pre-existing level or is upregulated in response to PDT stress; and (4) the signaling mechanisms involved in NOS expression and NO-induced resistance. This evidence concerns the gene NOS2 and neoplasm.