Opportunities in cancer gene therapy: inhibiting MDM2 and restoring p14ARF as a means to activate p53

Abstract The MDM2/p53/p14ARF axis represents a central regulatory network controlling cell-cycle progression, genomic stability, and tumor suppression, and is frequently deregulated in human cancers. In many malignancies, particularly those retaining wild-type TP53 , p53 activity is functionally suppressed through MDM2 overexpression or CDKN2A (p14ARF) loss, events that may be reversed in order to activate this pathway. This review explores the biological basis of the MDM2/p53/p14ARF axis and its relevance as a target for gene therapy and multimodal treatment strategies. While gene therapy for the restoration of p53 has been extensively explored, the use of genetic interventions for the inhibition of MDM2 or the restoration of p14ARF is underrepresented, though they have the potential to re-establish DNA damage responses, promote apoptosis, and enhance tumor sensitivity to chemotherapy and radiotherapy. In addition, p53 activation is now recognized as a contributor to immunogenic cell death and modulation of the tumor microenvironment. Laboratory and early clinical studies demonstrate that inhibition of MDM2 and restoration of p14ARF by gene transfer can integrate tumor cytotoxicity with immune activation. Although large-scale clinical validation remains limited, current evidence supports the MDM2/p53/p14ARF axis as a promising, context-dependent target within biomarker-driven combination therapies rather than a standalone approach.