TP53 is the most frequently mutated gene in high-grade serous ovarian cancer, and the majority of these mutations result in overexpression of mutant p53. Therefore, therapies that can restore the wild-type activities from p53 mutants have the potential to cause p53-mediated tumor suppressive effects. Accordingly, prior studies have shown that APR-246 can bind to specific p53 mutants, restore wild-type activities, and cause tumor suppression in cancer cell lines with hot-spot mutations. However, systematic analysis of what other p53 mutants are responsive to APR-246 is currently lacking. Here, we used a TP53 mutagenesis library to perform functional genetic screens to identify TP53 mutants that are sensitive to APR-246. Our studies confirm weak p53-dependent cytotoxic/cytostatic effects in OVCAR5 but not in SKOV3 and CAOV3. Further analysis identified ferroptosis sensitivity as a major determinant of APR-246 sensitivity. This agrees with the known effect of APR-246 as a disruptor of the redox system. In ferroptosis-sensitive SKOV3 and CAOV3, p53-dependent effects are not observable because APR-246 acts primarily through its induction of ferroptosis. Only in OVCAR5, which is relatively insensitive to ferroptosis compared to SKOV3 and CAOV3, do we observe a p53-dependent effect of APR-246. This study demonstrates that p53-specific effects of APR-246 are only observable in a narrow dosing window, under a specific set of conditions. Collectively, our results highlight the limitation of APR-246 as a p53-rescuing drug because of its overwhelming off-target effects on the redox system at doses that are sufficient to induce ferroptosis but insufficient to rescue mutant p53.

TP53 is the most frequently altered tumor-suppressor gene in human cancer, yet efforts to therapeutically target p53 have yielded limited and inconsistent clinical success. We argue that this gap reflects not a lack of druggable biology, but an oversimplified conceptual framework that treats p53 as a binary wild-type versus mutant entity. Here, we synthesize emerging evidence supporting a model in which p53 operates across a spectrum of functional states defined by mutation class, allelic burden, isoform composition, aggregation propensity, post-translational regulation, and cellular context. These states shape distinct biological outputs, including transcriptional activity, dominant-negative and gain-of-function effects, immune modulation, and checkpoint dependency, which collectively determine therapeutic vulnerability. We review current strategies targeting the p53 pathway, including mutant p53 reactivation, targeted degradation, anti-aggregation approaches, immune-directed therapies, restoration of wild-type pathway activity, gene replacement, and synthetic lethal targeting of DNA damage response dependencies. Clinical and preclinical evidence highlights key limitations of each approach, including stoichiometric constraints, mutation specificity, context-dependent efficacy, and adaptive resistance. Notably, emerging evidence from preclinical and correlative clinical studies suggests that therapeutic outcomes may be more closely associated with p53 functional state than with TP53 mutation status alone. We further emphasize the emerging roles of p53 isoforms and the tumor immune microenvironment as critical modifiers of p53 activity and determinants of treatment response. Collectively, these insights support a paradigm shift toward mechanism-matched, biomarker-stratified strategies that align therapeutic modality with the operative p53 network. Future progress will depend on integrating multi-parameter diagnostics with rational combination therapies to fully exploit p53 as a central vulnerability in cancer.