With these caveats in mind, this review aimed to highlight the plethora of mechanisms by which a TP53 mutation interacts with a given tissue or disease context, reorganizes the regulatory network that it encounters, induces characteristic alterations to the tumor cell secretome, and, thereby, remodels the tumor stroma into a less hostile microenvironment that is more supportive for tumor expansion and metastasis. This evidence concerns the gene TP53 and neoplasm.