Considering the observed non-overlapping p53 mutations in either tumors or stromal compartment of the TME, such as tumor or CAFs, we propose that combination of p53 reactivators with MDM2 inhibitors will broaden the spectrum of p53 activation in the TME regardless of the p53 status, thereby likely representing a more effective approach for promoting antitumor immunity and overcoming tumor-induced immune tolerance. The gene discussed is MDM2; the disease is neoplasm.