A pan-cancer benchmark of integrated ferroptosis, cuproptosis and disulfidptosis prognostic signatures

Integrated prognostic signatures combining ferroptosis, cuproptosis, and disulfidptosis are increasingly reported in oncology as advances in risk stratification, yet their added value over simpler pathway-specific or proliferation-related models remains unclear. Here, we developed an integrated regulated cell-death signature and evaluated it through an adversarial pan-cancer benchmark. Using the TCGA pan-cancer cohort comprising 9,808 tumours across 33 cancer types, we curated 118 genes associated with the three cell-death programmes, characterised inter-pathway crosstalk, and derived a 26-gene LASSO-Cox risk signature. The model showed reproducible prognostic performance across cancers, with a pan-cancer concordance index of 0.573 (95% CI, 0.552-0.594), and was independently validated in METABRIC and CGGA cohorts, remaining significant after adjustment for standard clinical variables. However, benchmarking revealed that the integrated signature, although superior to size-matched random gene sets (empirical p < 0.001), did not outperform a ferroptosis-only model (DeLong p = 0.81), indicating no measurable gain from pathway integration. Moreover, much of the prognostic signal reflected tumour proliferation rather than regulated cell death. After adjustment for the proliferation meta-signature (meta-PCNA), ferroptosis performance declined from 0.573 to 0.504, while the integrated model decreased to 0.554. High-risk tumours were more sensitive to anti-proliferative drugs, and the risk score was most strongly associated with E2F, MYC, and G2M target programmes. The signature stratified prognosis but did not predict immune-checkpoint blockade response in IMvigor210 (AUC {approx} 0.50). Importantly, the underlying biology was not merely a modelling artefact. Signature genes showed concordance with protein abundance in CPTAC cohorts, and the three cell-death programmes co-varied within individual malignant cells, with correlations ranging from {rho} = 0.46 to 0.66. Overall, our findings indicate that integrated multi-death signatures are reproducible and biologically grounded, yet prognostically redundant and substantially confounded by proliferation. This study provides a cautionary benchmark for the rapidly expanding use of composite regulated cell-death signatures in cancer prognosis.