Multi-omics identification of an immunogenic cell death-related signature for clear cell renal cell carcinoma in the context of 3P medicine and based on a 101-combination machine learning computational framework

Clear cell renal cell carcinoma (ccRCC) is a prevalent urological malignancy associated with a high mortality rate. The lack of a reliable prognostic biomarker undermines the efficacy of its predictive, preventive, and personalized medicine (PPPM/3PM) approach. Immunogenic cell death (ICD) is a specific type of programmed cell death that is tightly associated with anti-cancer immunity. However, the role of ICD in ccRCC remains unclear. Based on AddModuleScore, single-sample gene set enrichment analysis (ssGSEA), and weighted gene co-expression network (WGCNA) analyses, ICD-related genes were screened at both the single-cell and bulk transcriptome levels. We developed a novel machine learning framework that incorporated 10 machine learning algorithms and their 101 combinations to construct a consensus immunogenic cell death-related signature (ICDRS). ICDRS was evaluated in the training, internal validation, and external validation sets. An ICDRS-integrated nomogram was constructed to provide a quantitative tool for predicting prognosis in clinical practice. Multi-omics analysis was performed, including genome, single-cell transcriptome, and bulk transcriptome, to gain a more comprehensive understanding of the prognosis signature. We evaluated the response of risk subgroups to immunotherapy and screened drugs that target specific risk subgroups for personalized medicine. Finally, the expression of ICD-related genes was validated by qRT-PCR. We identified 131 ICD-related genes at both the single-cell and bulk transcriptome levels, of which 39 were associated with overall survival (OS). A consensus ICDRS was constructed based on a 101-combination machine learning computational framework, demonstrating outstanding performance in predicting prognosis and clinical translation. ICDRS can also be used to predict the occurrence, development, and metastasis of ccRCC. Multivariate analysis verified it as an independent prognostic factor for OS, progression-free survival (PFS), and disease-specific survival (DSS) of ccRCC. The ICDRS-integrated nomogram provided a quantitative tool in clinical practice. Moreover, we observed distinct biological functions, mutation landscapes, and immune cell infiltration in the tumor microenvironment between the high- and low-risk groups. Notably, the immunophenoscore (IPS) score showed a significant difference between risk subgroups, suggesting a better response to immunotherapy in the high-risk group. Potential drugs targeting specific risk subgroups were also identified. Our study constructed an immunogenic cell death-related signature that can serve as a promising tool for prognosis prediction, targeted prevention, and personalized medicine in ccRCC. Incorporating ICD into the PPPM framework will provide a unique opportunity for clinical intelligence and new management approaches.