A pan-cancer multi-omic SuperLearner for regulated cell death survival topologies.
INTRODUCTION: Regulated cell death (RCD) pathways influence tumor progression and immune modulation. We previously constructed a signature database mapping 25 RCD forms across seven multi-omic layers and 33 tumor types (CancerRCDShiny). Despite their ability to identify risk populations, translating these signatures into personalized clinical workflows requires a shift from cohort stratification to individualized risk mapping by modeling patient risk (survival topologies) to capture the non-linear dynamics of RCD signatures. METHODS: We engineered a pan-cancer multi-omic SuperLearner pipeline across 33 cancer types. Phase I performed zero-leakage harmonization and groupwise imputation to prevent cross-cohort amalgamation. Phase II deployed Elastic Net-regularized Cox regression as a CANARY diagnostic to map proportional hazards failures. Strata with a 35% missingness barrier entered Phase III, deploying a Quadripartite ensemble: Random Survival Forests, XGBoost, Survival-Boruta, and Multi-Task Logistic Regression, fused within an Elastic Net Multi-View Meta-Learner (MVL), with post-hoc TreeSHAP and LIME interpretability. RESULTS: The CANARY diagnostic demonstrated the structural invalidity of pan-cancer geometric proportional hazards. Across 96 admissible strata, Phase III executed algorithmic displacement: continuous multi-omic topologies suppressed static genomic mutations and copy number variations (85.7% vs. 0.0% apex retention). The MVL stabilized predictions against extreme variance; LIME surrogate validations (R 2 < 0.10) confirmed the systematic failure of linear interpretative proxies. N-dimensional TreeSHAP interaction mapping exposed synergistic and antagonistic rescue trajectories defining individualized Survival Topologies, which were invisible to additive models. The architecture was deployed as CancerRCDPredictor, a digital molecular tumor board with integrated LLM capabilities. The MVL SuperLearner achieved a median C-index of 0.749 (IQR: 0.722-0.836) across 96 modelable strata, with 95% bootstrap confidence intervals confirming precision (median width: 0.052) and permutation significance in 93.8% of strata (p < 0.001). External CPTAC validation across ten cancer types demonstrated significant cross-cohort generalizability in clear cell renal carcinoma (KIRC; C-index 0.675, p = 0.017) and modest performance across the remaining adequately powered cancers (median 0.582), underscoring the need for larger multi-institutional validation cohorts. CONCLUSION: This pan-cancer multi-omic SuperLearner bypasses linear topological failures, advancing beyond generalized stratification to establish a deterministically mapped architecture for predicting RCD-related survival topologies. Through the CancerRCDPredictor interface, multi-omic insights translate into individualized survival topology exploration, providing a foundation for future precision oncology validation.